Ophthalmic formulations of cetirizine and methods of use

ABSTRACT

The present invention provides stable topical formulations of cetirizine that provide a comfortable formulation when instilled in the eye and is effective in the treatment of allergic conjunctivitis and/or allergic conjunctivitis. The invention further provides methods of treating allergic conjunctivitis and/or allergic rhinoconjunctivitis in a subject in need of such treatment by topical application of the cetirizine formulations of the invention directly to the eye.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation of Ser. No. 17/018,865 filed Sep. 11,2020 which is a continuation of Ser. No. 16/839,954 filed Apr. 3, 2020,which is a divisional of U.S. application Ser. No. 16/001,679 filed Jun.6, 2018, and issued as U.S. Pat. No. 10,675,279 on Jun. 9, 2020, whichis a continuation of U.S. application Ser. No. 15/456,249, filed on Mar.10, 2017, which is a continuation of U.S. application Ser. No.14/982,258, filed on Dec. 29, 2015, and issued as U.S. Pat. No.9,750,684 on Sep. 5, 2017, which is a continuation of U.S. applicationSer. No. 12/724,128, filed on Mar. 15, 2010, and issued as U.S. Pat. No.9,254,286 on Feb. 9, 2016, which claims priority to U.S. ProvisionalApplication No. 61/161,006, filed Mar. 17, 2009 and U.S. ProvisionalApplication No. 61/174,850, filed May 1, 2009, the contents of which areeach hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The invention relates to compositions comprising cetirizine, alone or incombination with one or more additional active agents such as a steroidand/or a vasoconstrictor, and methods for using the same for treatingallergic conjunctivitis and allergic rhinoconjunctivitis.

BACKGROUND OF THE INVENTION

There exists a need for topical ophthalmic pharmaceutical products toeffectively treat allergic conjunctivitis, a disorder that presents withboth acute allergic symptoms (i.e., seasonal allergy) and late phaseinflammatory reactions (i.e., chronic, refractory or persistentallergy), as well as allergic rhinoconjunctivitis. It has been estimatedthat 46% (˜70 million) of the adult allergy patients in the UnitedStates suffer from both the acute and late phase conditions of allergicconjunctivitis, whereas only 19% suffer from only acute or late phaseallergy, respectively. It is estimated that allergic rhinoconjunctivitis(a combination of ocular and nasal symptoms) may occur in up to 90% ofpatients with allergies. The average age of allergy sufferers—between 20and 40 years—coincides with the average age of the work force and themost productive period of an individual's life.

Both seasonal and perennial allergic conjunctivitis (ocular allergies)are characterized by itchy, red, swollen, and watery eyes. Allergicrhinitis (nasal allergies) manifests as a runny nose, sneezing,congestion, and similar symptoms. It can be difficult for a physician todistinguish allergic conjunctivitis from allergic rhinoconjunctivitisbecause both allergic reactions can occur simultaneously or be triggeredby the same types of stimuli. It is further difficult to distinguishacute allergic symptoms from late phase symptoms of allergicconjunctivitis, as each of these conditions can persist simultaneouslyor morph back and forth in any given individual. The signs and symptomsof allergic conjunctivitis and allergic rhinoconjunctivitis cansignificantly impact the quality of life of patients, from socialinteractions, productivity at work and school, to the ability to performvisual tasks such as working on a computer or reading.

Acute symptoms of allergic conjunctivitis are characterized by theclinical signs and symptoms of eye itching, redness, and swelling. Latephase or allergic inflammation reactions of allergic conjunctivitisinclude redness, lid swelling and tearing, and in some cases itching, aswell as the predominance of congestion in the nose. Acute allergicsymptoms are predominantly caused by the activation of mast cells, whichwhen stimulated by an allergen (pollen, dust, dander) releases a host ofsubstances that produce the signs and symptoms of allergicconjunctivitis (itching, redness, swelling, and tearing). Histamine isthe primary mediator released and stimulates receptors on nerve endingsand blood vessels to produce itching and redness. There are twohistamine receptors that have been identified on the ocular surface. H1receptors on nerve endings lead to itching, and H1 and H2 receptors onblood vessels lead to dilation of the blood vessels, leading to redness,and leakage of fluid from the vessels into the surrounding tissueproducing swelling. Late phase inflammatory reactions are mediated byactivation of inflammatory cells.

Like allergic conjunctivitis, allergic rhinoconjunctivitis is anallergen-induced, mast cell-mediated response. The reaction is triggeredwhen airborne allergens bind to antibodies attached to the surface ofmast cells in the eye and/or nose. Mast cells, in turn, release chemicalmediators, which account for the immediate reaction in sensitizedindividuals exposed to allergen. Some of these mediators, such ashistamine, directly affect blood vessels and nerves, leading to thesigns and symptoms of allergic disease. Other released mediators causethe influx of white blood cells to the site, which leads to sustainedsymptoms in severe cases and particularly congestion in the nose.

Allergic conjunctivitis and rhinoconjunctivitis may also co-exist withother external ocular conditions and diseases, such as dry eye, orirritations caused by pollutants or other causes. This leads to acompromised tear film, which serves to protect the ocular surface fromallergens.

Currently available treatments for eye allergy include: drops which canwash allergens off the ocular surface and act as a barrier for the eye(e.g. artificial tears), drugs which block histamine from binding to thehistamine receptors (e.g. antihistamines), drugs that block the releaseof histamine and other substances from the mast cell (e.g. mast cellstabilizers), drugs with multiple modes of action (e.g.antihistamine/mast cell stabilizing agents), and drugs that can activelyconstrict blood vessels thus reducing redness and swelling (e.g.vasoconstrictors). The criteria which may be considered in evaluatingthe appropriateness of an agent for a patient include: efficacy at onsetof action, duration of action, how well it controls the individual signsand symptoms of allergic conjunctivitis, comfort of the formulation wheninstilled in the eye, and safety of the formulation when instilled inthe eye. The comfort of an ophthalmic product depends on the activepharmaceutical ingredient itself, as well as the nature of theformulation and the vehicle that makes up the product. Oralantihistamines have been shown to induce decreased tear production andlead to dryness of the ocular surface, which can exacerbate oculardiscomfort and can make the eye susceptible to irritation by anophthalmic product.

The currently available treatments which contain a single active agent,such as an antihistamine or a mast cell stabilizer, typically providerelief for only acute allergic conjunctivitis and don't address thesigns and symptoms of the late phase inflammatory reactions (i.e.,chronic, refractory, or persistent allergy).

Currently available treatments for allergic rhinoconjunctivitis includeeyedrops, nasal sprays, and systemic oral agents. Currently approvedanti-allergy eyedrops are indicated for ocular allergy and nasal spraysare targeted for nasal allergy. Systemic agents, while they haveindications to treat both nasal and ocular symptoms, several wellcontrolled clinical trials conducted to ophthalmic standards have shownthat systemic antihistamines are inferior to eyedrops in treating theocular signs and symptoms (Spangler et al., Clin. Ther. 25(8), 2245-2267(2003), are not in fact clinically effective on eye allergy, andactually have been shown by objective measures to reduce tear productionon the eye by 50%, causing ocular dryness (Ousler et al, Ann AllergyAsthma Immunol. November; 93(5):460-4 (2004)). Further studies haveshown that the combination of an eyedrop and nasal steroid is moreeffective than a systemic agent in treating the ocular and nasal signsand symptoms of allergy (Lanier et al. Clin. Ther. 24(7), 1161-1174(2002)).

Cetirizine hydrochloride is a racemic selective H1 receptor inverseagonist which functions as an antihistamine. It is a major metabolite ofhydroxyzine and a derivative of piperazine. The levorotary enantiomer ofcetirizine is known as levocetirizine. Cetirizine hydrochloride is FDAapproved for oral use and is used as a systemic antihistamine for thetreatment of allergies, hay fever, angioedema, and urticaria. It hasbeen historically difficult to prepare cetirizine as an ophthalmicsolution with satisfactory safety and stability profiles. Cetirizine hasthe disadvantage of forming aggregates in solution at low concentrations(typically less than 1% (w/v)), thereby decreasing the stability as anaqueous solution. Moreover, higher concentrations of cetirizine (1% andabove) are strongly irritating and thus unsuitable for direct ocular ornasal administration. U.S. Pat. No. 5,419,898 addresses these issues byusing a cyclodextrin compound to increase the solubility and stabilityof cetirizine for ophthalmic use. However, a cyclodextrin-free stableophthalmic formulation containing cetirizine as the only activeingredient that is both comfortable in the eye and effective to mitigatethe symptoms of allergic conjunctivitis has never been previouslyachieved.

There thus exists a need to develop an effective, stable yet comfortableand safe cetirizine formulations for ophthalmic administration for thetreatment of allergic conjunctivitis (i.e., the acute phase, the lateinflammatory phase, or both) and allergic rhinoconjunctivitis. Suchformulations for administration directly to the eye would beadvantageous over systemic oral formulations and nasal sprays due tofaster action and avoidance of the side effects associated with systemicadministration.

SUMMARY OF THE INVENTION

The present invention provides comfortable topical ophthalmicformulations for the treatment of both acute and late phase signs ofallergic conjunctivitis as well as rhinoconjunctivitis which contain acombination of ingredients which act synergistically to relieve thesigns and symptoms of allergic conjunctivitis and/orrhinoconjunctivitis, particularly ocular itching and/or nasal symptoms(e.g., itchy, running nose, sneezing, nasal/sinus congestion). Inparticular, the formulations described herein provide stableformulations comprising a low concentration of cetirizine suitable forophthalmic use in a comfortable ophthalmic formulation when instilled inthe eye.

The present invention is based on the surprising discovery that stabletopical ophthalmic formulations comprising a low concentration ofcetirizine can be prepared without the use of a cyclodextrin or othersolubilizer compound, that is both comfortable when instilled in the eyeand effective to mitigate the symptoms of allergic conjunctivitis and/orrhinoconjunctivitis, particularly ocular itching and/or nasal symptoms(e.g., itchy, running nose, sneezing, nasal/sinus congestion). Theinvention also provides methods for the treatment of allergicconjunctivitis and/or rhinoconjunctivitis in a subject in need of suchtreatment by administering a cetirizine formulation of the inventiondirectly to the eye of the subject. Surprisingly, once a day dosing ofthe low concentration cetirizine formulations of the invention iseffective to mitigate the symptoms of allergic conjunctivitis and/orrhinoconjunctivitis, particularly ocular itching and/or nasal symptoms(e.g., itchy, running nose, sneezing, nasal/sinus congestion).

The invention also provides stable ophthalmic formulations of cetirizinein combination with one or more active ingredients including but notlimited to a vasoconstrictor such naphazoline or oxymetazoline, and/or asteroid such as fluticasone, or combinations thereof. The combinationformulations of cetirizine are effective in mitigating the signs andsymptoms of both acute and late phase allergic conjunctivitis, such asocular itching, redness, chemosis, and lid swelling, and nasal symptoms,as well as allergic rhinoconjunctivitis.

More specifically, the combination formulations of the invention (e.g.,cetirizine and fluticasone) provide a comprehensive treatment benefitfor both acute and late phase reactions of allergic conjunctivitis, thatcannot be achieved by the use of a single anti-allergic, or other activeagent, alone. Antihistamines and mast cell stabilizers such ascetirizine do not effectively block all allergic and pro-inflammatorymediators from the mast cell. Cetirizine, and other antihistamines andmast cell stabilizers, effectively masks itching but has minimal effectson redness, tearing, swelling and inflammation. However, when cetirizineis combined with another active agent which can halt the transcriptionand production of inflammatory mediators and down-regulate theproduction of anti-inflammatory mediator, such as a steroid (e.g.,fluticasone), treatment of the signs and symptoms of acute and latephase allergic conjunctivitis ((i.e., the aggregate disease) isachieved. Likewise, such combination formulations provide acomprehensive treatment benefit for rhinoconjunctivitis that cannot beachieved by the use of a single anti-allergic, or other active agentalone, for these same reasons.

In one particular embodiment, the cetirizine formulation of theinvention comprises a stable ophthalmic formulation of cetirizine as theonly active ingredient at a concentration of 0.01% to 1.0% (w/v),preferably 0.05% to 0.5% (w/v), or any specific value within saidranges. Preferably, cetirizine is in the form of cetirizinehydrochloride or dihydrochloride. Surprisingly, the stable cetirizineformulation is achieved without the use of a cyclodextrin, or othersolubilizing compound, which were described as being required in U.S.Pat. No. 5,419,898.

In another particular embodiment, the invention provides a stableophthalmic formulation of cetirizine in combination with fluticasone.Preferably, cetirizine is in the form of cetirizine hydrochloride ordihydrochloride. In certain embodiments, cetirizine is present in theformulation at a concentration of 0.05% to 1.0% (w/v), or any specificvalue within said range. For example, cetirizine is formulated at aconcentration of 0.050% to 0.075%, 0.075% to 0.1%, 0.1% to 0.25%, 0.25%to 0.50%, 0.50% to 0.75%, or 0.75% to 1.0% (w/v), or any specific valuewithin said ranges). In particular embodiments, cetirizine is formulatedat a concentration of 0.05%, 0.1%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%,0.45%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0% (w/v). In certainembodiments, fluticasone is present in the formulation at aconcentration of 0.001% to 1.0% (w/v), or any specific value within saidrange. Preferably, fluticasone is present in the formulation at aconcentration of 0.001% and 0.2% (w/v), or any specific value withinsaid range. For example, fluticasone is formulated at a concentration of0.001%, 0.005%, 0.01%, 0.015%, 0.025%, or 0.2% (w/v). In a particularembodiment, cetirizine is present in the formulation at a concentrationof 0.1% (w/v) and fluticasone is present in the formulation at aconcentration of 0.005% (w/v). In another particular embodiment,cetirizine is present in the formulation at a concentration of 0.25%(w/v) and fluticasone is present in the formulation at a concentrationof 0.01% (w/v). The stable cetirizine/fluticasone formulation isachieved without the use of a cyclodextrin, or other solubilizingcompound. The cetirizine alone, and combination formulations of theinvention (e.g., cetirizine/fluticasone) are stable and comfortable uponinstillation in the eye. Surprisingly, the cetirizine/fluticasoneformulations of the invention do not increase intraocular pressure inthe eye after repeated use (e.g., after 14 days). As such the cetirizinecombination formulations of the invention are safe for ocular use.

In certain embodiments, the cetirizine alone and cetirizine combinationformulations of the invention are formulated in a vehicle comprising 1%Polyethylene Glycol 400, NF; 0.2% Dibasic Sodium Phosphate, Anhydrous,USP; 0.25% Hypromellose, USP; 0.1% Polysorbate 80, NF; 1.2% to 1.8%Glycerin (or any specific value within said range), USP; 0.025% EdetateDisodium, USP; 0.01% Benzalkonium Chloride, NF (pH 7.0).

In some embodiments, the stable ophthalmic cetirizine formulations ofthe invention comprise a tear substitute. In particular embodiments, thetear substitute is hydroxypropylmethyl cellulose (Hypromellose or HPMC).According to some embodiments, the concentration of HPMC ranges fromabout 0.1% to about 2% w/v, or any specific value within said range.According to some embodiments, the concentration of HPMC ranges fromabout 0.5% to about 1% w/v, or any specific value within said range. Ina preferred embodiments, the concentration of HPMC ranges from about0.1% to about 1.0% w/v, or any specific value within said range (e.g.,0.1-0.2%, 0.2-0.3%, 0.3-0.4%, 0.4-0.5%, 0.5-0.6%, 0.6-0.7%, 0.7-0.8%,0.8-0.9%, 0.9-1.0%; about 0.2%, about 0.21%, about 0.22%, about 0.23%,about 0.24%, about 0.25%, about 0.26%, about 0.27%, about 0.28%, about0.29%, about 0.30%, about 0.70%, about 0.71%, about 0.72%, about 0.73%,about 0.74%, about 0.75%, about 0.76%, about 0.77%, about 0.78%, about0.79%, about 0.80%, about 0.81%, about 0.82%, about 0.83%, about 0.84%,about 0.85%, about 0.86%, about 0.87%, about 0.88%, about 0.89%, orabout 0.90%).

In another particular embodiment the tear substitute is carboxymethylcellulose (CMC). According to some embodiments, the concentration of CMCranges from about 0.1% to about 2% w/v, or any specific value withinsaid range. According to some embodiments, the concentration of CMCranges from about 0.1% to about 1% w/v, or any specific value withinsaid range. In a preferred embodiments, the concentration of CMC rangesfrom about 0.7% to about 0.9% w/v, or any specific value within saidrange (i.e., about 0.70%, about 0.71%, about 0.72%, about 0.73%, about0.74%, about 0.75%, about 0.76%, about 0.77%, about 0.78%, about 0.79%,about 0.80%, about 0.81%, about 0.82%, about 0.83%, about 0.84%, about0.85%, about 0.86%, about 0.87%, about 0.88%, about 0.89%, or about0.90%).

In yet another particular embodiment, the stable ophthalmic cetirizineformulations of the invention comprise a polymeric, mucoadhesivevehicle. Examples of mucoadhesive vehicles suitable for use in themethods or formulations of the invention include but are not limited toaqueous polymeric suspensions comprising one or more polymericsuspending agents including without limitation dextrans, polyethyleneglycol, polyvinylpyrolidone, polysaccharide gels, Gelrite®, cellulosicpolymers, and carboxy-containing polymer systems. In a particularembodiment, the polymeric suspending agent comprises a crosslinkedcarboxy-containing polymer (e.g., polycarbophil). In another particularembodiment, the polymeric suspending agent comprises a polyethyleneglycol (PEG). Examples of cross-linked carboxy-containing polymersystems suitable for use in the topical stable ophthalmic cetirizineformulations of the inventioninclude but are not limited to Noveon AA-1,Carbopol®, and/or DuraSite® (InSite Vision).

Optionally, the formulations of the invention contain a preservative. Inparticular embodiments the preservative is benzalkonium chloride or aderivative thereof (e.g., Polyquad®), or a stabilized oxychloro complex(e.g., Purite®).

According to some embodiments, the ophthalmic formulations of thepresent invention has a viscosity that ranges from about 30 to about 150centipoise (cpi), preferably about 50 to about 120 cpi, even morepreferably about 60 to about 115 cpi (or any specific value within saidranges). According to preferred embodiments, the ophthalmic formulationsof the present invention has a viscosity that ranges from about 60 toabout 80 cpi, or any specific value within said range (i.e., about 60cpi, about 61 cpi, about 62 cpi, about 63 cpi, about 64 cpi, about 65cpi, about 66 cpi, about 67 cpi, about 68 cpi, about 69 cpi, about 70cpi, about 71 cpi, about 72 cpi, about 73 cpi, about 74 cpi, about 75cpi, about 76 cpi, about 77 cpi, about 78 cpi, about 79 cpi, or about 80cpi).

The invention also provides methods of treating and preventing thesymptoms of allergic conjunctivitis by administering a stable cetirizineformulation of the invention (i.e., cetirizine alone or in combinationwith an additional active agent such as a steroid (e.g., fluticasone) ora vasoconstrictor (e.g., naphazoline or oxymetazoline) directly to theeye of a subject in need of such treatment or prevention. Preferably,the formulation of the invention is administered once a day (q.d.). Incertain embodiments, the methods of the invention (i.e., administrationof a formulation of the invention directly to the eye) are alsoeffective to treat nasal symptoms associated with allergicconjunctivitis. The invention also provides methods of treating andpreventing the symptoms of allergic rhinoconjunctivitis by administeringa stable cetirizine formulation of the invention (i.e., cetirizine aloneor in combination with an additional active agent such as a steroid(e.g., fluticasone) or a vasoconstrictor (e.g., naphazoline oroxymetazoline) directly to the eye of a subject in need of suchtreatment or prevention. By providing a treatment option in eye dropform, the present invention will improve quality of life in patientswith allergic rhinoconjunctivitis/rhinitis (See e.g., Berger et al.,Ann. Allergy Asthma Immunol. October 95(4), 361-71 (2005).

The invention further provides kits comprising a pharmaceuticalcomposition of cetirizine formulated for ophthalmic use and instructionsfor such use. Other features and advantages of the invention will becomeapparent from the following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a line graph depicting the efficacy of a 0.1% cetirizineformulation reducing of ocular itching as compared to a vehicle control.The mean ocular itching score (scale of 0 to 4) is shown at 0, 3, 5, and7 minutes after conjunctival challenge with allergen; FIG. 1B is a linegraph depicting the efficacy of a 0.1% cetirizine formulation reducingconjunctival redness as compared to a vehicle control

FIG. 2 is a line graph depicting the comfort profile of a 0.1%cetirizine formulation upon instillation in the eye as compared to avehicle control. The comfort of the formulation is indicated on asubjective scale of 0 to 10 (0=very comfortable; 10=very uncomfortable).The mean drop comfort score is shown at 0, 1, 2 minutes after additionof a drop of the cetirizine formulation of the invention.

FIGS. 3A and 3B depict a study design (screening and evaluation) fortesting the efficacy of Fluticasone 0.001%, 0.005% and 0.01% as comparedto vehicle in reducing ocular and nasal symptoms of ocular allergy in anallergic conjunctivitis model.

FIG. 4 is a line graph comparing the efficacy of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle in reducing ocular itchingassessed on a scale of 0 (no itching) to 4 (severe itching) over time.

FIG. 5 is a line graph comparing the efficacy of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle in reducing conjunctivalredness, assessed on a scale of 0 (no redness) to 4 (severe redness)over time.

FIG. 6 is line graph comparing the efficacy of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle in reducing lidswelling,assessed on a scale of 0 (no swelling) to 3 (severe swelling) over time.

FIG. 7 is a line graph comparing the efficacy of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle in reducing nasal congestion,assessed on a scale of 0 (no congestion) to 4 (severe congestion) overtime.

FIG. 8 is a bar graph summarizing the results shown in FIGS. 3-7.

FIG. 9 is a line graph comparing the efficacy of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle in reducing ciliary redness,assessed on a scale of 0 (no redness) to 4 (severe redness) over time.

FIG. 10 is a line graph comparing the efficacy of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle in reducing episcleral redness,assessed on a scale of 0 (no redness) to 4 (severe redness) over time.

FIG. 11 is a line graph comparing the efficacy of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle in reducing chemosis, assessedon a scale of 0 (none) to 4 (severe) over time.

FIG. 12 is a line graph comparing the efficacy of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle in reducing watery eyes,assessed on a scale of 0 (none) to 4 (severe) over time.

FIG. 13 is a bar graph summarizing the results shown in FIGS. 9-11.

FIG. 14 is a line graph comparing the efficacy of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle in reducing rhinorrhea, assessedon a scale of 0 (none) to 4 (severe) over time.

FIG. 15 is a line graph comparing the efficacy of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle in reducing ear or palatepruritis, assessed on a scale of 0 (none) to 4 (severe) over time.

FIG. 16 is a line graph comparing the efficacy of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle in reducing nasal pruritis,assessed on a scale of 0 (none) to 4 (severe) over time.

FIG. 17 is a line graph comparing the efficacy of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle on total nasal score, assessedon a scale of 0 (no nasal symptoms) to 16 (multiple nasal symptoms) overtime.

FIG. 18 is a bar graph summarizing the results shown in FIGS. 14-17.

FIG. 19 is a line graph comparing the efficacy of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle on peak nasal inspiratory flow(PNIF).

FIG. 20 a line graph comparing the drop comfort of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle, assessed on a scale of 0(extremely comfortable) to 10 (extremely uncomfortable) over time atVisit 2.

FIG. 21 a line graph comparing the drop comfort of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle, assessed on a scale of 0(extremely comfortable) to 10 (extremely uncomfortable) over time atVisit 3.

FIG. 22 is a chart summarizing the incidence of adverse eventsassociated with instillation of Fluticasone 0.001%, 0.005% and 0.01% inthe eye.

FIG. 23 is a bar graph summarizing the effects of Fluticasone 0.001%,0.005% and 0.01% as compared to vehicle on intraocular pressure.

FIG. 24 is a bar graph summarizing the effects of a 0.1%cetirizine/0.005% fluticasone formulation (low dose) and a 0.25%cetirizine/0.01% fluticasone formulation (high dose) on conjunctivalhyperemia, chemosis, discharge, and lid swelling after three days ofdosing, as compared to 0.1% cetirizine alone, 0.005% fluticasone alone,a leading commercial antihistamine for treating allergic conjunctivitis(Pataday®; olopatadine 0.2%), a commercially available steroid (PredForte®; prednisolone acetate 1%) and a vehicle control.

FIG. 25 is a bar graph summarizing the effects of a 0.1%cetirizine/0.005% fluticasone formulation (low dose) and a 0.25%cetirizine/0.01% fluticasone formulation (high dose) on conjunctivalhyperemia, chemosis, discharge, and lid swelling after three days ofdosing, as compared to 0.1% cetirizine alone, 0.005% fluticasone alone,and vehicle control.

FIG. 26 is a bar graph summarizing the effects of a 0.1%cetirizine/0.005% fluticasone formulation (low dose) on conjunctivalhyperemia, chemosis, discharge, and lid swelling after three days ofdosing, as compared to 0.1% cetirizine alone, 0.005% fluticasone alone,and vehicle control.

FIG. 27 is a bar graph summarizing the sum of clinical exam scores for a0.1% cetirizine/0.005% fluticasone formulation (low dose) and a 0.25%cetirizine/0.01% fluticasone formulation (high dose), 0.1% cetirizinealone formulation, 0.005% fluticasone alone formulation, an olopatadine0.2% formulation, a prednisolone acetate 1% formulation and a vehiclecontrol.

FIG. 28 is a bar graph summarizing the sum of clinical exam scores for a0.1% cetirizine/0.005% fluticasone formulation (low dose) and a 0.25%cetirizine/0.01% fluticasone formulation (high dose), 0.1% cetirizinealone formulation, 0.005% fluticasone alone formulation, and a vehiclecontrol.

FIG. 29 is a line graph depicting the comfort profile of a 0.1%cetirizine/0.005% fluticasone formulation (low dose) and a 0.25%cetirizine/0.01% fluticasone formulation (high dose) upon instillationin the eye as compared to controls. The comfort of the formulation isindicated on a subjective scale of 0 to 10 (0=very comfortable; 10=veryuncomfortable).

DETAILED DESCRIPTION OF THE INVENTION

The invention is based in part on the discovery that low concentrationsof cetirizine (i.e., less than 1%) can be prepared as a stableophthalmic formulation, without the use of a cyclodextrin or othersolubilizing compound. Such formulations are comfortable and safe forocular use and effective at reducing the symptoms of allergicconjunctivitis and/or allergic rhinoconjunctivitis, particularly ocularitching and/or nasal symptoms (e.g., itchy, running nose, sneezing,nasal/sinus congestion).

The historical difficulty in preparing cetirizine as an ophthalmicsolution with satisfactory safety and stability profiles is wellrecognized in the art due to the fact that cetirizine aggregates insolution at low concentrations, and is highly irritating to the ocularsurface at high concentrations, being a strong acid. Without intendingto be bound by any theory, it was believed necessary to reduce thepossibility of salt formation and metal based degradation in order toarrive at a stable formulation. As such, the addition of counter ions ormetal based buffers that could promote salt formation, precipitation, ormetal based degradation were minimized or excluded from the cetirizineformulations of the invention. Furthermore, it was discovered that thepH could be adjusted to approximately 7.0 with no adverse effects onstability, to improve the comfort of the formula.

The invention features novel topical ophthalmic formulations comprisingan effective amount of cetirizine, or a pharmaceutically acceptable saltthereof, in a pharmaceutically acceptable carrier. Pharmaceuticallyacceptable cetirizine salts include cetirizine hydrochloride orcetirizine dihydrochloride. In particular embodiments, the inventionprovides stable ophthalmic formulations of cetirizine as the only activeagent in the formulations. The invention also features ophthalmicformulations of cetirizine in combination with one or more additionalactive ingredients selected from oxymetazoline, naphazoline andfluticasone. Such combination formulations are effective in furthermitigating the acute and late phase signs and symptoms of allergicconjunctivitis, such as ocular itching, redness, chemosis, lid swellingand nasal symptoms. Such formulations are also effective in mitigatingthe signs and symptoms of rhinoconjunctivitis, such as runny nose,sneezing, nasal/sinus congestion and red, watery and/or itchy eyes.

The comfort, safety, efficacy, solubility, and stability of theophthalmic formulations of the invention could not have been predictedby one skilled in the art. Many antihistamines have been developed overthe years by various companies for different indications. However, notall of these can be formulated or are effective as an eyedrop. Likewisenot all antihistamines have the same duration of action. For example thepotent antihistamine levocabastine has a duration of 2-4 hours; recentlyapproved bepotastine (Bepreve®-ISTA), indicated for twice daily dosing,has an 8 hour duration; olopatadine 0.1% (Patanol®) indicated for twicedaily dosing, has an 8 hour duration; and olopatadine 0.2%)(Pataday®,indicated for once daily dosing, has a 16 hour duration of action.Therefore the efficacy is not predictable. In one study (Berdy et al,1990), a panel of antihistamines were screened yet only a few weresuitable for the eye based on comfort, formulation, irritation, andefficacy. As evidenced by Berdy et al., one skilled in the art could nothave predicted which of the antihistamines would be ideal for ocular useor for treating ocular allergy. The invention is based, in part, uponthe surprising and unpredictable discovery that an antihistamine and asteroid, when combined, act synergistically to treat both the acute andlate phase reactions of allergic conjunctivitis, as well as allergicrhinoconjunctivitis.

In some embodiment, the cetirizine formulations of the inventioncomprise one or more tear substitute components. The cetirizinecomponent provides relief of the symptoms of allergic conjunctivitis,and the one or more tear substitute component provides ocular surfaceprotection via enhancement of the tear film (as evident by increasedtear film break up time), and can act to enhance dwell time on theocular surface thus increasing duration of activity. An effective amountof such formulations may be used to treat and/or prevent signs andsymptoms associated with acute and/or late phase allergic conjunctivitisand/or general eye irritation, and can also be used to treat another eyedisorder if it contains a drug for that disorder. An effective amount ofsuch formulations may also be used to treat and/or prevent signs andsymptoms of allergic rhinoconjunctivitis. Such formulations provide acomfortable ophthalmic formulation when instilled in the eye and haveenhanced efficacy and/or duration of action over formulations ofcetirizine that are not combined with such other agents.

The superior efficacy of the combination cetirizine/tear substituteformulations is attributed to, among other things, the synergisticeffect of the combination of ingredients in them. The combination ofcetirizine and tear substitute, act synergistically to provide a longerdwell time of the cetirizine on the ocular surface, thus increasingduration and efficacy of action, and to prolong the integrity of thetear film thereby providing protection of the ocular surface (e.g., byincreasing the tear film break up time and/or the Ocular ProtectionIndex). As such, the compositions of the invention are comfortable uponinstillation into the eye, and may be used for relief of acute orchronic allergic conjunctivitis, and are particularly suitable for bothintermittent and long term use.

Formulations

In the context of this patent all concentrations are given for thecetirizine free base. The concentration for the cetirizine salt (e.g.cetirizine hydrochloride or dihydrochoride) can be calculated bymultiplying the free base concentration by 1.188. e.g. 0.1% cetirizinefree base is equivalent to 0.1188% cetirizine hydrochloride salt(0.1%×1.188=0.11881%).

Preferably, the ophthalmic formulations according to the presentinvention are formulated as solutions, suspensions, ointments, gels,emulsions, oils, and other dosage forms for topical administration.Aqueous solutions are generally preferred, based on ease of formulation,as well as a patient's ability to easily administer such compositions bymeans of instilling one to two drops of the solutions in the affectedeyes. However, the compositions may also be suspensions, viscous orsemi-viscous gels, or other types of solid or semisolid compositions orsustained release devices or mechanisms that are placed in or around theeye. In one embodiment, the cetirizine formulations of the invention areaqueous formulations. The aqueous formulations of the invention aretypically more than 50%, preferably more than 75%, and most preferablymore than 90% by weight water. Preferably, the aqueous formulation doesnot contain a cyclodextrin or other solubilizer compound. Stable aqueousformulations of cetirizine are achieved by minimizing/excluding theaddition of counter ions or metal based buffers that could promote saltformation, precipitation, or metal based degradation. In anotherembodiment, the cetirizine formulations are lyophilized formulations.

Active Agents

Cetirizine is the primary active agent in the ophthalmic formulations ofthe present invention, and in certain embodiments, the only active agentin the formulations of the invention. In certain embodiments of theinvention, cetirizine, or a pharmaceutically acceptable salt thereof, isformulated at a concentration of 0.01% to 1.0% (w/v). Preferably,cetirizine is in the form of cetirizine hydrochloride ordihydrochloride. In certain embodiments, cetirizine is formulated at aconcentration of 0.05% to 0.075%, 0.075% to 0.1%, 0.1% to 0.25%, 0.25%to 0.50%, 0.50% to 0.75%, or 0.75% to 1.0% (w/v). In particularembodiments, cetirizine is formulated at a concentration of 0.05% to1.0% (w/v), or any specific value within said range. For example,cetirizine is formulated at a concentration of 0.05%, 0.1%, 0.2%, 0.25%,0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, or 1.0% (w/v).(w/v). In one embodiment, the cetirizine formulation of the inventioncomprises cetirizine hydrochloride or dihydrochloride as the only activeingredient at a concentration of 0.01% to 1.0% (w/v), preferably 0.05%to 0.5% (w/v), more preferably 0.1% to 0.25% (w/v) (or any specificvalue within said ranges).

Cetirizine may be formulated with other active agents as describedherein. For example, cetirizine may be formulated with one or moreadditional anti-allergic agents. The term “anti-allergenic agent” refersto a molecule or composition that treats allergic conjunctivitis and/orrhinoconjunctivitis or reduces a symptom of allergic conjunctivitisand/or rhinoconjunctivitis. The term “allergic conjunctivitis” refers toany allergic disease of the eye, e.g., seasonal/perennial allergicconjunctivitis, vernal keratoconjunctivitis, giant papillaryconjunctivitis, perennial allergic conjunctivitis and atopickeratoconjunctivitis. The signs and symptoms of ocular allergies includechemosis, eye itching, tearing, redness and swelling, and may alsoco-exist with nasal symptomatology. The term “allergicrhinoconjunctivitis” refers to a combination of nasal and ocularsymptoms characterized by inflammation of the lining of the tissue ofthe eyes and nose due to an allergy or infection, causing nasaldischarge, mucus, sneezing, irritation, and red, water, itchy eyes.Non-limiting examples of anti-allergic agents include “antihistamines”or drugs which block histamine from binding to the histamine receptors,“mast cell stabilizers” or drugs that block the release of histamine andother substances from the mast cell, “drugs with multiple modes ofaction” or drugs that are antiallergenic agents having multiple modes ofaction (e.g. drugs that are antihistamines and mast cell stabilizers,drugs with antihistamine, mast cell stabilizing and anti-inflammatoryactivity, etc.), steroids, and nonsteroidal anti-inflammatory drugs or“NSAIDs.”

In certain embodiments, cetirizine is formulated with one or moreadditional active agents selected from a mast cell stabilizer such asnedocromil, iodoxamide, cromolyn, or cromolyn sodium; a non-steroidalanti-inflammatory drug (“NSAID”) such as diclofenac or ketorolactromethamine, bromfenac, or nepafenac; a vasoconstrictor such asnaphazoline, antolazine, tetrahydozoline or oxymetazoline; a topicalsteroid such as fluticasone, beclomethasone, budesonide, diflorasone,triaminicinolone, clobetasol, difluprednate, prednisolone,dexamethasone, halobetasol, or mometasone; an antihistimine such asantazoline, astemizole, azelastine, bepotastine, bilastine,brompheniramine, chlorpheniramine, clemastine, desloratidine,dexbrompheniramine, diphenhydramine, doxylamine, ebastine, emedastine,epinastine, fexofenadine, hydroxyzine, ketotifen, levocabastine,levocetirizine, loratidine, mequitazine, mizolastine, olopatadine,oxatomide, phenindamine, pheniramine, pyrilamine, terfenidine, andtriprolidine; or an alpha-adrenergic agonist such as epinephrine,fenoxazoline, indanazoline, naphazoline, oxedrine, phenylephrine,tefazoline, tetryzoline, tramazoline, tymazoline, oxymetazoline, orxylometazoline.

In certain embodiments, cetirizine is formulated with one or moreadditional active agents such as a vasoconstrictor (e.g., naphazoline oroxymetazoline), or a steroid (e.g., fluticasone).

Naphazoline (in the hydrochloride form) is the common name for2-(1-naphthylmethyl)-2-imidazoline hydrochloride. It is asympathomimetic agent with marked alpha adrenergic activity. It is avasoconstrictor with a rapid action in reducing swelling when applied tomucous membrane. It acts on alpha-receptors in the arterioles of theconjunctiva to produce constriction, resulting in decreased congestion.Oxymetazoline is a selective alpha-1 agonist and partial alpha-2 agonisttopical decongestant, used in the form of oxymetazoline hydrochloride incommercially available nasal sprays. Oxymetazoline has sympathomimeticproperties, and thus constricts the blood vessels of the nose andsinuses via activation of alpha-2 adrenergic receptors. Fluticasone is apotent synthetic corticosteroid often prescribed as treatment for asthmaand allergic rhinitis.

In certain embodiments, cetirizine is formulated at a concentration offrom 0.05% to 0.50% (w/v), in combination with naphazoline at aconcentration of from 0.01% to 0.5% (w/v), preferably 0.01% to 0.1%(w/v), preferably 0.05% to 0.1% (w/v), more preferably 0.09% to 0.1%(w/v). In particular embodiments, cetirizine is formulated at aconcentration of 0.01%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.15%,0.20%, 0.25%, 0.30%, 0.35%, 0.45%, or 0.50% (w/v) in combination withnaphazoline at a concentration of 0.01%, 0.02%, 0.03%, 0.04%, 0.05%,0.06% 0.07%, 0.08%, 0.09% or 0.10% (w/v).

In certain embodiments, cetirizine is formulated at a concentration offrom 0.05% to 0.50% (w/v) in combination with oxymetazoline at aconcentration of from 0.01% to about 0.2% (w/v), preferably 0.01% to0.1% (w/v), more preferably 0.03% to 0.05% (w/v). In particularembodiments, cetirizine is formulated at a concentration of 0.05%,0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%,0.45%, or 0.50% (w/v) in combination with oxymetazoline at aconcentration of 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07% 0.09%or 0.10% (w/v).

In certain embodiments, cetirizine is formulated at a concentration offrom 0.05% to 0.50% (w/v) in combination with fluticasone at aconcentration of from 0.001% to 1.0% (w/v), preferably 0.001% to 0.2%(w/v), or any specific value within said ranges. In particularembodiments, cetirizine is formulated at a concentration of 0.05%,0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%,0.45%, or 0.50% (w/v) in combination with fluticasone at a concentrationof 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.01%, 0.015%, 0.05%, 0.1%,0.2%, 0.5%, or 1% (w/v). In a particular embodiment, the cetirizine ispresent in the formulation at a concentration of 0.25% (w/v) and thefluticasone is present in the formulation at a concentration of 0.01%(w/v). In another particular embodiment, the cetirizine is present inthe formulation at a concentration of 0.1% (w/v) and the fluticasone ispresent in the formulation at a concentration of 0.005% (w/v).

In certain embodiments, the viscosity of the cetirizine formulations ofthe invention (i.e. cetirizine alone or in combination with anadditional active agent) ranges from 1-50 centipoise (cpi), or anyspecific value within said range. In a particular embodiment, theviscosity of the cetirizine formulations of the invention range from5-30 cpi, preferably 10-20 cpi.

Excipients

In some embodiments, the cetirizine formulations of the inventioncomprise one or more pharmaceutically acceptable excipients. The termexcipient as used herein broadly refers to a biologically inactivesubstance used in combination with the active agents of the formulation.An excipient can be used, for example, as a solubilizing agent, astabilizing agent, a surfactant, a demulcent, a viscosity agent, adiluent, an inert carrier, a preservative, a binder, a disintegrant, acoating agent, a flavoring agent, or a coloring agent. Preferably, atleast one excipient is chosen to provide one or more beneficial physicalproperties to the formulation, such as increased stability and/orsolubility of the active agent(s). A “pharmaceutically acceptable”excipient is one that has been approved by a state or federal regulatoryagency for use in animals, and preferably for use in humans, or islisted in the U.S. Pharmacopia, the European Pharmacopia or anothergenerally recognized pharmacopia for use in animals, and preferably foruse in humans.

Further examples of excipients include certain inert proteins such asalbumins; hydrophilic polymers such as polyvinylpyrrolidone; amino acidssuch as aspartic acid (which may alternatively be referred to asaspartate), glutamic acid (which may alternatively be referred to asglutamate), lysine, arginine, glycine, and histidine; fatty acids andphospholipids such as alkyl sulfonates and caprylate; surfactants suchas sodium dodecyl sulphate and polysorbate; nonionic surfactants such assuch as TWEEN®, PLURONICS®, or a polyethylene glycol (PEG) designated200, 300, 400, or 600; a Carbowax designated 1000, 1500, 4000, 6000, and10000; carbohydrates such as glucose, sucrose, mannose, maltose,trehalose, and dextrins, including cyclodextrins; polyols such asmannitol and sorbitol; chelating agents such as EDTA; and salt-formingcounter-ions such as sodium.

Examples of carriers that may be used in the formulations of the presentinvention include water, mixtures of water and water-miscible solvents,such as C₁- to C₇-alkanols, vegetable oils or mineral oils comprisingfrom 0.5 to 5% non-toxic water-soluble polymers, natural products, suchas gelatin, alginates, pectins, tragacanth, karaya gum, xanthan gum,carrageenin, agar and acacia, starch derivatives, such as starch acetateand hydroxypropyl starch, and also other synthetic products, such aspolyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether,polyethylene oxide, preferably cross-linked polyacrylic acid, such asneutral Carbopol, or mixtures of those polymers. The concentration ofthe carrier is, typically, from 1 to 100000 times the concentration ofthe active ingredient.

In a particular embodiment, the carrier is a polymeric, mucoadhesivevehicle. Examples of mucoadhesive vehicles suitable for use in themethods or formulations of the invention include but are not limited toaqueous polymeric suspensions comprising one or more polymericsuspending agents including without limitation dextrans, polyethyleneglycol, polyvinylpyrolidone, polysaccharide gels, Gelrite®, cellulosicpolymers, and carboxy-containing polymer systems. In a particularembodiment, the polymeric suspending agent comprises a crosslinkedcarboxy-containing polymer (e.g., polycarbophil). In another particularembodiment, the polymeric suspending agent comprises polyethylene glycol(PEG). Examples of cross-linked carboxy-containing polymer systemssuitable for use in the topical stable ophthalmic cetirizineformulations of the inventioninclude but are not limited to Noveon AA-1,Carbopol®, and/or DuraSite® ((InSite Vision).

In particular embodiments, the cetirizine formulations of the inventioncomprise one or more excipients selected from among the following: atear substitute, a tonicity enhancer, a preservative, a solubilizer, aviscosity enhancing agent, a demulcent, an emulsifier, a wetting agent,a sequestering agent, and a filler. The amount and type of excipientadded is in accordance with the particular requirements of theformulation and is generally in the range of from about 0.0001% to 90%by weight.

Tear Substitutes

The term “tear substitute” refers to molecules or compositions whichlubricate, “wet,” approximate the consistency of endogenous tears, aidin natural tear build-up, or otherwise provide temporary relief of dryeye signs or symptoms and conditions upon ocular administration. Avariety of tear substitutes are known in the art and include, but arenot limited to: monomeric polyols, such as, glycerol, propylene glycol,and ethylene glycol; polymeric polyols such as polyethylene glycol;cellulose esters such hydroxypropylmethyl cellulose, carboxymethylcellulose sodium and hydroxy propylcellulose; dextrans such as dextran70; water soluble proteins such as gelatin; vinyl polymers, such aspolyvinyl alcohol, polyvinylpyrrolidone, and povidone; and carbomers,such as carbomer 934P, carbomer 941, carbomer 940 and carbomer 974P.Many such tear substitutes are commercially available, which include,but are not limited to cellulose esters such as Bion Tears®, Celluvisc®,Genteal®, OccuCoat®, Refresh®, Systane®, Teargen II®, Tears Naturale®,Tears Natural II®, Tears Naturale Free®, and TheraTears®; and polyvinylalcohols such as Akwa Tears®, HypoTears®, Moisture Eyes®, MurineLubricating®, and Visine Tears®, Soothe®. Tear substitutes may also becomprised of paraffins, such as the commercially available Lacri-Lube@ointments. Other commercially available ointments that are used as tearsubstitutes include Lubrifresh PM®, Moisture Eyes PM® and Refresh PM®.

In one preferred embodiment of the invention, the tear substitutecomprises hydroxypropylmethyl cellulose (Hypromellose or HPMC).According to some embodiments, the concentration of HPMC ranges fromabout 0.1% to about 2% w/v, or any specific value within said range.According to some embodiments, the concentration of HPMC ranges fromabout 0.5% to about 1.5% w/v, or any specific value within said range.According to some embodiments, the concentration of HPMC ranges fromabout 0.1% to about 1% w/v, or any specific value within said range.According to some embodiments, the concentration of HPMC ranges fromabout 0.6% to about 1% w/v, or any specific value within said range. Ina preferred embodiments, the concentration of HPMC ranges from about0.1% to about 1.0% w/v, or any specific value within said range (i.e.,0.1-0.2%, 0.2-0.3%, 0.3-0.4%, 0.4-0.5%, 0.5-0.6%, 0.6-0.7%, 0.7-0.8%,0.8-0.9%, 0.9-1.0%; about 0.2%, about 0.21%, about 0.22%, about 0.23%,about 0.24%, about 0.25%, about 0.26%, about 0.27%, about 0.28%, about0.29%, about 0.30%, about 0.70%, about 0.71%, about 0.72%, about 0.73%,about 0.74%, about 0.75%, about 0.76%, about 0.77%, about 0.78%, about0.79%, about 0.80%, about 0.81%, about 0.82%, about 0.83%, about 0.84%,about 0.85%, about 0.86%, about 0.87%, about 0.88%, about 0.89%, orabout 0.90%).

For example, without limitation, a tear substitute which compriseshydroxypropyl methyl cellulose is GenTeal® lubricating eye drops.GenTeal® (CibaVision-Novartis) is a sterile lubricant eye dropcontaining hydroxypropylmethyl cellulose 3 mg/g and preserved withsodium perborate. Other examples of an HPMC-based tear are provided.

In another preferred embodiment, the tear substitute comprisescarboxymethyl cellulose sodium. For example, without limitation, thetear substitute which comprises carboxymethyl cellulose sodium isRefresh® Tears. Refresh® Tears is a lubricating formulation similar tonormal tears, containing a, mild non-sensitizing preservative,stabilised oxychloro complex (Purite®), that ultimately changes intocomponents of natural tears when used.

In a preferred embodiment, the tear substitute, or one or morecomponents thereof, is an aqueous solution having a viscosity in a rangewhich optimizes efficacy of supporting the tear film while minimizingblurring, lid caking, etc. Preferably, the viscosity of the tearsubstitute, or one or more components thereof, ranges from 1-150centipoise (cpi), e.g., 5-150 cpi, 5-130 cpi, 30-130 cpi, 50-120 cpi,60-115 cpi (or any specific value within said ranges). In a particularembodiment, the viscosity of the tear substitute, or one or morecomponents thereof, is about 70-90 cpi, or any specific value withinsaid range (for example without limitation, 85 cpi).

Viscosity may be measured at a temperature of 20° C.+/−1° C. using aBrookfield Cone and Plate Viscometer Model VDV-III Ultra⁺ with a CP40 orequivalent Spindle with a shear rate of approximately22.50+/−approximately 10 (1/sec), or a Brookfield Viscometer ModelLVDV-E with a SC4-18 or equivalent Spindle with a shear rate ofapproximately 26+/−approximately 10 (1/sec). Alternatively, viscositymay be measured at 25° C.+/−1° C. using a Brookfield Cone and PlateViscometer Model VDV-III Ultra⁺ with a CP40 or equivalent Spindle with ashear rate of approximately 22.50+/−approximately 10 (1/sec), or aBrookfield Viscometer Model LVDV-E with a SC4-18 or equivalent Spindlewith a shear rate of approximately 26+/−approximately 10 (1/sec).

In some embodiments, the tear substitute, or one or more componentsthereof is buffered to a pH 5.0 to 9.0, preferably pH 5.5 to 7.5, morepreferably pH 6.0 to 7.0 (or any specific value within said ranges),with a suitable salt (e.g., phosphate salts). In some embodiments, thetear substitute further comprises one or more ingredients, includingwithout limitation, glycerol, propyleneglycerol, glycine, sodium borate,magnesium chloride, and zinc chloride.

Salts, Buffers, and Preservatives

The formulations of the present invention may also containpharmaceutically acceptable salts, buffering agents, or preservatives.Examples of such salts include those prepared from the following acids:hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic,salicylic, citric, boric, formic, malonic, succinic, and the like. Suchsalts can also be prepared as alkaline metal or alkaline earth salts,such as sodium, potassium or calcium salts. Examples of buffering agentsinclude phosphate, citrate, acetate, and 2-(N-morpholino)ethanesulfonicacid (MES).

For the adjustment of the pH, preferably to a physiological pH, buffersmay especially be useful. The pH of the present solutions should bemaintained within the range of 4.0 to 8.0, more preferably about 5.5 to7.5, more preferably about 6.0 to 7.0. Suitable buffers may be added,such as boric acid, sodium borate, potassium citrate, citric acid,sodium bicarbonate, TRIS, and various mixed phosphate buffers (includingcombinations of Na₂HPO₄, NaH₂PO₄ and KH₂PO₄) and mixtures thereof.Borate buffers are preferred. Generally, buffers will be used in amountsranging from about 0.05 to 2.5 percent by weight, and preferably, from0.1 to 1.5 percent.

In certain embodiments, the topical formulations additionally comprise apreservative. A preservative may typically be selected from a quaternaryammonium compound such as benzalkonium chloride, benzoxonium chloride orthe like. Benzalkonium chloride is better described as:N-benzyl-N-(C₈-C₁₈ alkyl)-N,N-dimethylammonium chloride. Furtherexamples of preservatives include antioxidants such as vitamin A,vitamin E, vitamin C, retinyl palmitate, and selenium; the amino acidscysteine and methionine; citric acid and sodium citrate; and syntheticpreservatives such as thimerosal, and alkyl parabens, including forexample, methyl paraben and propyl paraben. Other preservatives includeoctadecyldimethylbenzyl ammonium chloride, hexamethonium chloride,benzethonium chloride, phenol, catechol, resorcinol, cyclohexanol,3-pentanol, m-cresol, phenylmercuric nitrate, phenylmercuric acetate orphenylmercuric borate, sodium perborate, sodium chlorite, alcohols, suchas chlorobutanol, butyl or benzyl alcohol or phenyl ethanol, guanidinederivatives, such as chlorohexidine or polyhexamethylene biguanide,sodium perborate, Polyquad®, Germal®II, sorbic acid and stabilizedoxychloro complexes (e.g., Purite®). Preferred preservatives arequaternary ammonium compounds, in particular benzalkonium chloride orits derivative such as Polyquad (see U.S. Pat. No. 4,407,791),alkyl-mercury salts, parabens and stabilized oxychloro complexes (e.g.,Purite®). Where appropriate, a sufficient amount of preservative isadded to the ophthalmic composition to ensure protection againstsecondary contaminations during use caused by bacteria and fungi.

In particular embodiments, the cetirizine formulations of the inventioncomprise a preservative selected from among the following: benzalkoniumchloride, 0.001% to 0.05%; benzethonium chloride, up to 0.02%; sorbicacid, 0.01% to 0.5%; polyhexamethylene biguanide, 0.1 ppm to 300 ppm;polyquaternium-1 (Omamer M)-0.1 ppm to 200 ppm; hypochlorite,perchlorite or chlorite compounds, 500 ppm or less, preferably between10 and 200 ppm); stabilized hydrogen peroxide solutions, a hydrogenperoxide source resulting in a weight % hydrogen peroxide of 0.0001 to0.1% along with a suitable stabilizer; alkyl esters of p-hydroxybenzoicacid and mixtures thereof, preferably methyl paraben and propyl paraben,at 0.01% to 0.5%; chlorhexidine, 0.005% to 0.01%; chlorobutanol, up to0.5%; and stabilized oxychloro complex (Purite®) 0.001% to 0.5%.

In another embodiment, the topical formulations of this invention do notinclude a preservative. Such formulations would be useful for patientswho wear contact lenses, or those who use several topical ophthalmicdrops and/or those with an already compromised ocular surface (e.g. dryeye) wherein limiting exposure to a preservative may be more desirable.

Viscosity Enhancing Agents and Demulcents

In certain embodiments, viscosity enhancing agents may be added to thecetirizine formulations of the invention. Examples of such agentsinclude polysaccharides, such as hyaluronic acid and its salts,chondroitin sulfate and its salts, dextrans, various polymers of thecellulose family, vinyl polymers, and acrylic acid polymers.

In certain embodiments, the cetirizine formulations of the inventioncomprise ophthalmic demulcents and/or viscosity enhancing polymersselected from one or more of the following: cellulose derivatives suchas carboxymethycellulose (0.01 to 5%) hydroxyethylcellulose (0.01% to5%), hydroxypropyl methylcellulose or hypromellose (0.01% to 5%), andmethylcelluose (0.02% to 5%); dextran 40/70 (0.01% to 1%); gelatin(0.01% to 0.1%); polyols such as glycerin (0.01% to 5%), polyethyleneglycol 300 (0.02% to 5%), polyethylene glycol 400 (0.02% to 5%),polysorbate 80 (0.02% to 3%), propylene glycol (0.02% to 3%), polyvinylalcohol (0.02% to 5%), and povidone (0.02% to 3%); hyaluronic acid(0.01% to 2%); and chondroitin sulfate (0.01% to 2%).

Viscosity of the stable ophthalmic cetirizine formulations of theinvention may be measured according to standard methods known in theart, such as use of a viscometer or rheometer. One of ordinary skill inthe art will recognize that factors such as temperature and shear ratemay effect viscosity measurement. In a particular embodiment, viscosityof the is measured at 20° C.+/−1° C. using a Brookfield Cone and PlateViscometer Model VDV-III Ultra+ with a CP40 or equivalent Spindle with ashear rate of approximately 22.50+/−approximately 10 (1/sec), or aBrookfield Viscometer Model LVDV-E with a SC4-18 or equivalent Spindlewith a shear rate of approximately 26+/−approximately 10 (1/sec). Inanother embodiment, viscosity of the ophthalmic formulations of theinvention is measured at 25° C.+/−1° C. using a Brookfield Cone andPlate Viscometer Model VDV-III Ultra+ with a CP40 or equivalent Spindlewith a shear rate of approximately 22.50+/−approximately 10 (1/sec), ora Brookfield Viscometer Model LVDV-E with a SC4-18 or equivalent Spindlewith a shear rate of approximately 26+/−approximately 10 (1/sec).

Tonicity Enhancers

Tonicity is adjusted if needed typically by tonicity enhancing agents.Such agents may, for example be of ionic and/or non-ionic type. Examplesof ionic tonicity enhancers are alkali metal or earth metal halides,such as, for example, CaCl₂), KBr, KCl, LiCl, Nal, NaBr or NaCl, Na₂SO₄or boric acid. Non-ionic tonicity enhancing agents are, for example,urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose. Theaqueous solutions of the present invention are typically adjusted withtonicity agents to approximate the osmotic pressure of normal lachrymalfluids which is equivalent to a 0.9% solution of sodium chloride or a2.5% solution of glycerol. An osmolality of about 225 to 400 mOsm/kg ispreferred, more preferably 280 to 320 mOsm.

Solubilizing Agents

The topical formulation may additionally require the presence of asolubilizer, in particular if one or more of the ingredients tends toform a suspension or an emulsion. Suitable solubilizers include, forexample, tyloxapol, fatty acid glycerol polyethylene glycol esters,fatty acid polyethylene glycol esters, polyethylene glycols, glycerolethers, polysorbate 20, polysorbate 80 or mixtures of those compounds.In a preferred embodiment, the solubilizer is a reaction product ofcastor oil and ethylene oxide, for example the commercial productsCremophor EL® or Cremophor RH40®. Reaction products of castor oil andethylene oxide have proved to be particularly good solubilizers that aretolerated extremely well by the eye. In another embodiment, thesolubilizer is tyloxapol or a cyclodextrin. The concentration useddepends especially on the concentration of the active ingredient. Theamount added is typically sufficient to solubilize the activeingredient. For example, the concentration of the solubilizer is from0.1 to 5000 times the concentration of the active ingredient.Preferably, the solubilizer is not a cyclodextrin compound (for examplealpha-, beta- or gamma-cyclodextrin, e.g. alkylated, hydroxyalkylated,carboxyalkylated or alkyloxycarbonyl-alkylated derivatives, or mono- ordiglycosyl-alpha-, beta- or gamma-cyclodextrin, mono- ordimaltosyl-alpha-, beta- or gamma-cyclodextrin or panosyl-cyclodextrin).

Examples of Formulations

In a preferred embodiment, the cetirizine formulation comprisescetirizine at 0.05% to 0.25% (w/v), glycerin at 0.1% to 5% (v/v) (e.g.,0.1% to 3% (v/v) or any specific value within said range), and water. Inparticular embodiments the cetirizine formulation of the invention doesnot contain a cyclodextrin or other solubilizing compound. Optionally,the formulation also comprises a preservative such as benzalkoniumchloride at 0.005% to 0.02% (w/v) or its derivative (e.g., Polyquad®),or a stabilized oxychloro complex such as Purite®. In a particularembodiment, the cetirizine formulation comprises cetirizine at 0.1%(w/v), glycerin at 1.2% to 3% (v/v), and water. In another particularembodiment, the cetirizine 0.1% (w/v), glycerin 1.2% to 3% (v/v), andwater formulation also comprises benzalkonium chloride at 0.01% (w/v) ora stabilized, oxychloro complex (e.g., Purite®). The pH of theformulation is between 5.0 and 7.5. for example, the pH of theformulation is 5, 5.5, 6.0, 6.5 or 7.0.

In a specific embodiment, the cetirizine formulation comprisescetirizine at 0.1% (w/v), glycerin at 2.125% (v/v), benzalknoiumchloride at 0.01% (w/v), q.s. with water. In one embodiment, thecetirizine formulation comprises cetirizine as the only activeingredient at 0.05% to 0.25% (w/v) and optionally one or more tearsubstitutes or a mucoadhesive, polymeric compound (e.g., Durasite®).Preferably, the cetirizine formulations do not contain a cyclodextrin orother solubilizing compound.

Where the formulation comprises one or more tear substitutes, the tearsubstitute preferably contains hydroxypropylmethyl cellulose orcarboxymethyl cellulose or both. In some embodiments, thehydroxypropylmethyl cellulose or carboxymethyl cellulose is present at aconcentration of 0.5% to 1% (w/v) (or any specific value within saidrange) and the resulting viscosity of the solution is 60-80 cpi. In aparticular embodiment, the hydroxypropylmethyl cellulose orcarboxymethyl cellulose is present at a concentration of 0.7% to 0.9%.In another particular embodiment, the hydroxypropylmethyl cellulose orcarboxymethyl cellulose is present at a concentration of 0.1% to 0.7%and the resulting viscosity of the solution is 10-30 cpi. Optionally,the formulation also comprises a preservative, preferably benzalkoniumchloride at a concentration of from 0.005% to 0.02% (w/v) (or anyspecific value within said range) or its derivative (e.g., Polyquad®),or a stabilized oxychloro complex (e.g., Purite®). The pH of theformulation is between 5.0 and 7.5. For example, the pH of theformulation is 5, 5.5, 6.0, 6.5 or 7.0.

In another preferred embodiment, the cetirizine formulation comprisescetirizine at 0.05% to 0.25% (w/v), naphazoline at 0.01% to 0.2% (w/v),glycerin at 0.1% to 5% (v/v) (e.g., 0.1% to 3% (v/v) or any specificvalue within said range), and water. Preferably, thecetirizine/naphazoline formulation does not contain a cyclodextrin orother solubilizing compound. Optionally, the formulation also comprisesbenzalkonium chloride at 0.005% to 0.02% (w/v) or its derivative (e.g.,Polyquad®), or a stabilized oxychloro complex such as Purite®. In aparticular embodiment, the cetirizine formulation comprises cetirizineat 0.1% (w/v), naphazoline at 0.09% (w/v), glycerin at 1.2% to 3% (v/v),and water. In another particular embodiment, the cetirizine 0.1% (w/v),naphazoline 0.09% (w/v), glycerin at 1.2% to 3% (v/v), and waterformulation also comprises benzalkonium chloride at 0.01% (w/v) or astabilized oxychloro complex such as Purite®. The pH of the formulationis between 5.0 and 7.5. For example, the pH of the formulation is 5,5.5, 6.0, 6.5 or 7.0.

In yet another preferred embodiment, the cetirizine formulationcomprises cetirizine at 0.05% to 0.25% (w/v), naphazoline at 0.01% to0.2% (w/v), and one or more tear substitutes or a mucoadhesive polymericcompound (e.g., Durasite®). In particular embodiments the cetirizineformulation does not contain a cyclodextrin or other solubilizingcompound. Where the formulation comprises one or more tear substitutes,the tear substitute preferably contains hydroxypropylmethyl cellulose orcarboxymethyl cellulose, or both. In some embodiments, thehydroxypropylmethyl cellulose or carboxymethyl cellulose is present at aconcentration of 0.5% to 1% (w/v) (or any specific value within saidrange) and the resulting viscosity of the solution is 60-80 cpi. In aparticular embodiment, the hydroxypropylmethyl cellulose orcarboxymethyl cellulose is present at a concentration of 0.7% to 0.9%.Optionally, the formulation also comprises a preservative, preferablybenzalkonium chloride at a concentration of from 0.005% to 0.02% (w/v)(or any specific value within said range) or stabilised oxychlorocomplex)(Purite®). The pH of the formulation is between 5.0 and 7.5. Forexample, the pH of the formulation is 5, 5.5, 6.0, 6.5 or 7.0.

In yet another preferred embodiment, the cetirizine formulationcomprises cetirizine at 0.05% to 0.25% (w/v), oxymetazoline at 0.01% to0.1% (w/v), glycerin at 0.1% to 5% (v/v) (e.g., 0.1% to 3% (v/v) or anyspecific value within said range), and water. Preferably, thecetirizine/oxymetazoline formulation does not contain a cyclodextrin orother solubilizing compound. Optionally, the formulation also comprisesbenzalkonium chloride at 0.005% to 0.02% (w/v) or its derivative (e.g.,Polyquad®), or a stabilized, oxychloro complex (e.g., Purite®). In aparticular embodiment, the cetirizine formulation comprises cetirizineat 0.1% (w/v), oxymetazoline at 0.05% (w/v), glycerin at 1.2% to 3%(v/v), and water. In another particular embodiment, the cetirizine 0.1%(w/v), oxymetazoline 0.05% (w/v), glycerin 1.2% to 3% (v/v), and waterformulation also comprises benzalkonium chloride at 0.01% (w/v) or astabilized, oxychloro complex (e.g., Purite®). In certain embodiments,the pH of the formulation is between 5.0 and 7.5. For example, the pH ofthe formulation is 5, 5.5, 6.0, 6.5 or 7.0.

In still another preferred embodiment, the cetirizine formulationcomprises cetirizine at 0.05% to 0.25% (w/v), oxymetazoline at 0.01% to0.1% (w/v), and one or more tear substitutes or a mucoadhesive,polymeric compound (e.g., Durasite®). Preferably, thecetirizine/oxymetazoline formulation does not contain a cyclodextrin orother solubilizing compound. Where the formulation comprises one or moretear substitutes, the tear substitute preferably containshydroxypropylmethyl cellulose or carboxymethyl cellulose or both. Insome embodiments, the hydroxypropylmethyl cellulose or carboxymethylcellulose is present at a concentration of 0.5% to 1% (w/v) (or anyspecific value within said range) and the resulting viscosity of thesolution is 60-80 cpi. In a particular embodiment, thehydroxypropylmethyl cellulose or carboxymethyl cellulose is present at aconcentration of 0.7% to 0.9%. Optionally, the formulation alsocomprises a preservative, preferably benzalkonium chloride at aconcentration of from 0.005% to 0.02% (w/v) (or any specific valuewithin said range) or a stabilized oxychloro complex (Purite®). The pHof the formulation is between 5.0 and 7.5. For example, the pH of theformulation is 5, 5.5, 6.0, 6.5 or 7.0.

In still another preferred embodiment, the cetirizine formulationcomprises cetirizine at 0.05% to 0.5% (w/v), fluticasone at 0.001% to1.0% (w/v), glycerin at 0.1% to 5% (v/v) (e.g., 0.1% to 3% (v/v) or anyspecific value within said range), and water. Preferably, thecetirizine/fluticasone formulation does not contain a cyclodextrin orother solubilizing compound. Optionally, the formulation also comprisesbenzalkonium chloride at 0.005% to 0.02% (w/v) or its derivative (e.g.,Polyquad®), or a stabilized, oxychloro complex (e.g., Purite®). In aparticular embodiment, the cetirizine formulation comprises cetirizineat 0.1% (w/v), fluticasone at 0.005%, glycerin at 1.2% to 3% (v/v), andwater. In another particular embodiment, the cetirizine formulationcomprises cetirizine at 0.25% (w/v), fluticasone at 0.01% (w/v),glycerin at 1.2% to 3% (v/v), and water. Optionally, thecetirizine/fluticasone formulations also comprises benzalkonium chlorideat 0.01% (w/v) or a stabilized, oxychloro complex (e.g., Purite®). ThepH of the formulation is between 5.0 and 7.5. For example, the pH of theformulation is 5, 5.5, 6.0, 6.5 or 7.0.

In yet another preferred embodiment, the cetirizine formulationcomprises cetirizine at 0.05% to 0.5% (w/v), fluticasone at 0.001% to1.0% (w/v), preferably fluticasone 0.005%, and one or more tearsubstitutes or a mucoadhesive, polymeric compound (e.g., Durasite®).Preferably, the cetirizine/fluticasone formulation does not contain acyclodextrin or other solubilizing compound. Where the formulationcomprises one or more tear substitutes, the tear substitute preferablycontains hydroxypropylmethyl cellulose or carboxymethyl cellulose orboth. In some embodiments, the hydroxypropylmethyl cellulose orcarboxymethyl cellulose is present at a concentration of 0.5% to 1%(w/v) (or any specific value within said range) and the resultingviscosity of the solution is 60-80 cpi. In a particular embodiment, thehydroxypropylmethyl cellulose or carboxymethyl cellulose is present at aconcentration of 0.7% to 0.9%. Optionally, the formulation alsocomprises a preservative, preferably benzalkonium chloride at aconcentration of from 0.005% to 0.02% (w/v) (or any specific valuewithin said range) or stabilized oxychloro complex)(Purite®. The pH ofthe formulation is between 5.0 and 7.5. For example, the pH of theformulation is 5, 5.5, 6.0, 6.5 or 7.0.

In still another preferred embodiment, the cetirizine formulationcomprises 0.1% cetirizine, 0.005% fluticasone, 1% Polyethylene Glycol400, NF, 0.2% Dibasic Sodium Phosphate, Anhydrous, USP, 0.25%Hypromellose, USP, 0.1% Polysorbate 80, NF, 1.8% Glycerin, USP, 0.025%Edetate Disodium, USP, and 0.01% Benzalkonium Chloride, NF (pH 7.0).

In yet another preferred embodiment, the cetirizine formulationcomprises 0.25% cetirizine, 0.01% fluticasone, 1% Polyethylene Glycol400, NF, 0.2% Dibasic Sodium Phosphate, Anhydrous, USP, 0.25%Hypromellose, USP; 0.1% Polysorbate 80, NF, 1.2% Glycerin, USP, 0.025%Edetate Disodium, USP, and 0.01% Benzalkonium Chloride, NF (pH 7.0).

The formulations of the present invention provide for the chemicalstability of the formulated cetirizine and other optional active agents(e.g., napahzoline, oxymetazoline, fluticasone, or combinations thereof)of the formulation, without the use of a cyclodextrin or othersolubilizing compound. “Stability” and “stable” in this context refersto the resistance of the cetirizine and other optional active agents tochemical degradation under given manufacturing, preparation,transportation and storage conditions. The “stable” formulations of theinvention also preferably retain at least 90%, 95%, 98%, 99%, or 99.5%of a starting or reference amount under given manufacturing,preparation, transportation, and/or storage conditions. The amount ofcetirizine and other optional active agents can be determined using anyart-recognized method, for example, as UV-Vis spectrophotometry and highpressure liquid chromatography (HPLC).

In certain embodiments, the cetirizine formulations are stable attemperatures ranging from about 20 to 30° C. for at least 1 week, atleast 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, atleast 6 weeks, or at least 7 weeks. In other embodiments, the cetirizineformulations are stable at temperatures ranging from about 20 to 30° C.for at least 1 month, at least 2 months, at least 3 months, at least 4months, at least 5 months, at least 6 months, at least 7 months, atleast 8 months, at least 9 months, at least 10 months, at least 11months, or at least 12 months. In one embodiment, the formulation isstable for at least 3 months at 20-25° C.

In other embodiments, the cetirizine formulations are stable attemperatures ranging from about 2 to 8° C. for at least 1 month, atleast 2 months, at least 4 months, at least 6 months, at least 8 months,at least 10 months, at least 12 months, at least 14 months, at least 16months, at least 18 months, at least 20 months, at least 22 months, orat least 24 months. In one embodiment, the formulation is stable for atleast 2 months at 2 to 8° C.

In other embodiments, the cetirizine formulations are stable attemperatures of about −20° C. for at least 1 month, at least 2 months,at least 4 months, at least 6 months, at least 8 months, at least 10months, at least 12 months, at least 14 months, at least 16 months, atleast 18 months, at least 20 months, at least 22 months, or at least 24months. In one embodiment, the formulation is stable for at least 6-12months at −20° C.

In a particular embodiment, a cetirizine formulation of the invention isstable at temperatures of about 20-30° C. at concentrations up to 0.10%for at least 3 months. In another embodiment, the formulation is stableat temperatures from about 2-8° C. at concentrations up to 0.10% for atleast 6 months.

Methods of Use

The cetirizine formulations of the invention are useful for thetreatment and prevention of the signs and symptoms of both the acutephase (i.e., seasonal) and late phase inflammatory reactions (i.e.,chronic, persistent or refractory) of allergic conjunctivitis, such asocular itching, redness, and eyelid swelling, as well as associatednasal symptoms. The formulations of the invention are also useful forthe treatment and prevention of the signs and symptoms of allergicrhinoconjunctivitis, such as itchy, running nose, sneezing, nasal/sinuscongestion, and red, watery and/or itchy eyes.

The invention provides methods of treating or preventing allergicconjunctivitis and/or allergic rhinoconjunctivitis in a subject in needthereof comprising topically administering to the eye surface of thesubject a an ophthalmic formulation comprising an effective amount ofcetirizine. In certain embodiments, the administration of cetirizine tothe eye of a subject in need of treatment or prevention of allergicconjunctivitis and/or rhinoconjunctivitis is also effective to mitigateor reduce one or more nasal symptoms associated with the either allergy(e.g., itchy, running nose, sneezing and/or nasal/sinus congestion).Topical administration of the ophthalmic formulations directly to theeye of a subject will significantly reduce nasal signs and symptoms viadrainage from the ocular surface into the nasal cavity through thenasolacrimal duct (See e.g., Abelson et al., Clin. Ther. 25(3), 931-947(2003); Spangler et al., Clin. Ther. 25(8), 2245-2267 (2003); andCrampton et al., Clin Ther. November; 24(11):1800-8 (2002). Furthermore,significantly less active agent is required to treat the nasal symptomswhen instilled through the eye of a subject as compared toadministration through the nose of the subject. For example, each sprayof Flonase® (commercially available nasal spray comprising fluticasone)delivers 50 micrograms of fluticasone to the nasal cavity to treatallergic rhinitis and allergic rhinoconjunctivitis. In contrast, onedrop of a 0.005% fluticasone ophthalmic formulation (i.e., 2.5micrograms in a 500 microliter drop) has been shown to significantlyreduce nasal symptoms associated with ocular allergy when topicallyadministered directly to the eye (see Example 2 herein). As such, themethods of the present invention are more effective than the currentlyavailable treatment options for nasal symptoms of allergicconjunctivitis and allergic rhinoconjunctivitis.

The subject is preferably a human, but may be another mammal, forexample a dog, a cat, a horse, a rabbit, a mouse, a rat, or a non-humanprimate.

The formulations of the present invention contain an amount ofcetirizine, and optionally one or more additional active ingredients(for example without limitation a vasoconstrictor such as naphazoline oroxymetazoline, or a steroid such as fluticasone), that is effective forthe intended use (i.e., to mitigate the signs and symptoms of allergicconjunctivitis and/or rhinoconjunctivitis). In certain embodiments, oncea day administration of the formulations of the present invention iseffective to mitigate the symptoms of allergic conjunctivitis and/orrhinoconjunctivitis. However, particular dosages are also selected basedon a number of factors including the age, sex, species and condition ofthe subject. Effective amounts can also be extrapolated fromdose-response curves derived from in vitro test systems or from animalmodels. The term “effective amount” means an amount of cetirizine thatis sufficient to eliminate or reduce a symptom of allergicconjunctivitis and/or rhinoconjunctivitis. In certain embodiments, theeffective amount is the amount sufficient for the treatment orprevention of allergic conjunctivitis and/or rhinoconjunctivitis.“Treatment” in this context refers to reducing or ameliorating at leastone symptom of allergic conjunctivitis and/or rhinoconjunctivitis.“Prevention” in this context refers to a reduction in the frequency of,or a delay in the onset of, symptoms associated with allergicconjunctivitis and/or rhinoconjunctivitis, relative to a subject whodoes not receive the composition. The effective amount of cetirizine andother active agents in the formulation will depend on absorption,inactivation, and excretion rates of the drug as well as the deliveryrate of the compound from the formulation. Particular dosages may alsovary with the severity of the condition to be alleviated. It is to befurther understood that for any particular subject, specific dosageregimens should be adjusted over time according to the individual needand the professional judgment of the person administering or supervisingthe administration of the compositions. Typically, a dosing regimentwill be determined using techniques known to one skilled in the art.

Examples of dosing regimens that can be used in the methods of theinvention include, but are not limited to, once daily, twice daily,three times, and four times daily. In certain embodiments, the methodcomprises administering a cetirizine formulation of the invention to theeye of the subject once a day. In some embodiments, the administrationis 2 to 4 times a day.

In certain embodiments, once a day administration (q.d.) is effective tomitigate the symptoms of ocular and/or nasal allergy. However,particular dosages may also selected based on a number of factorsincluding the age, sex, species and condition of the subject. Effectiveamounts can also be extrapolated from dose-response curves derived fromin vitro test systems or from animal models.

The combined use of several active agents formulated into thecompositions of the present invention may reduce the required dosage forany individual component because the onset and duration of effect of thedifferent components may be complimentary. In such combined therapy, thedifferent active agents may be delivered together or separately, andsimultaneously or at different times within the day.

In a particular embodiment, a formulation comprising cetirizine as theonly active agent in the formulation is administered to the eye of asubject in need of treatment or prevention of an allergic conjunctivitisand/or rhinoconjunctivitis once daily (q.d.). In certain embodiments,the combination formulation is administered two to four times a day.

In another particular embodiment, cetirizine is formulated with one ormore of naphazoline, oxymetazoline or fluticasone, and administered tothe eye of a subject in need of treatment or prevention of allergicconjunctivitis and/or rhinoconjunctivitis once daily (q.d.). In certainembodiments, the combination formulation is administered two to fourtimes a day.

In a preferred embodiment, cetirizine is formulated with fluticasone andadministered to the eyed of a subject in need of treatment or preventionof allergic conjunctivitis and/or rhinoconjunctivitis. Surprisingly thecombination formulations of cetirizine and fluticasone as describedherein were more effective at relieving itching than could be predictedfrom the efficacy of each component individually. Even more surprisingwas the finding that lower doses of cetirizine and fluticasone were moreeffective at relieving ocular itching and associated nasal symptoms ofallergic conjunctivitis than higher doses of the individual componentsalone, or in combination. For example, as described in the Examples, a0.1% cetirizine/0.005% fluticasone formulation (low dose) was moreefficacious than 0.25% cetirizine/0.01% fluticasone formulation (highdose). Similarly, in a clinical study described herein, the efficacy of0.005% fluticasone was more efficacious than the higher dose 0.01%fluticasone.

Packaging

The formulations of the present invention may be packaged as either asingle dose product or a multi-dose product. The single dose product issterile prior to opening of the package and all of the composition inthe package is intended to be consumed in a single application to one orboth eyes of a patient. The use of an antimicrobial preservative tomaintain the sterility of the composition after the package is opened isgenerally unnecessary.

Multi-dose products are also sterile prior to opening of the package.However, because the container for the composition may be opened manytimes before all of the composition in the container is consumed, themulti-dose products must have sufficient antimicrobial activity toensure that the compositions will not become contaminated by microbes asa result of the repeated opening and handling of the container. Thelevel of antimicrobial activity required for this purpose is well knownto those skilled in the art, and is specified in official publications,such as the United States Pharmacopoeia (“USP”) and correspondingpublications in other countries. Detailed descriptions of thespecifications for preservation of ophthalmic pharmaceutical productsagainst microbial contamination and the procedures for evaluating thepreservative efficacy of specific formulations are provided in thosepublications. In the United States, preservative efficacy standards aregenerally referred to as the “USP PET” requirements. (The acronym “PET”stands for “preservative efficacy testing.”)

The use of a single dose packaging arrangement eliminates the need foran antimicrobial preservative in the compositions, which is asignificant advantage from a medical perspective, because conventionalantimicrobial agents utilized to preserve ophthalmic compositions (e.g.,benzalkonium chloride) may cause ocular irritation, particularly inpatients suffering from dry eye conditions or pre-existing ocularirritation. However, the single dose packaging arrangements currentlyavailable, such as small volume plastic vials prepared by means of aprocess known as “form, fill and seal”, have several disadvantages formanufacturers and consumers. The principal disadvantages of the singledose packaging systems are the much larger quantities of packagingmaterials required, which is both wasteful and costly, and theinconvenience for the consumer. Also, there is a risk that consumerswill not discard the single dose containers following application of oneor two drops to the eyes, as they are instructed to do, but instead willsave the opened container and any composition remaining therein forlater use. This improper use of single dose products creates a risk ofmicrobial contamination of the single dose product and an associatedrisk of ocular infection if a contaminated composition is applied to theeyes.

While the formulations of this invention are preferably formulated as“ready for use” aqueous solutions, alternative formulations arecontemplated within the scope of this invention. Thus, for example, theactive ingredients, surfactants, salts, chelating agents, or othercomponents of the ophthalmic solution, or mixtures thereof, can belyophilized or otherwise provided as a dried powder or tablet ready fordissolution (e.g., in deionized, or distilled) water. Because of theself-preserving nature of the solution, sterile water is not required.

Kits

The present invention provides a pharmaceutical pack or kit comprisingone or more containers filled with a liquid or lyophilized cetirizineformulation of the invention (i.e., a formulation comprising cetirizinealone or in combination with an additional active agent as describedherein). In one embodiment, the formulation is an aqueous formulation ofcetirizine. In one embodiment, the formulation is lyophilized. Inpreferred embodiments the liquid or lyophilized formulation is sterile.In one embodiment, the kit comprises a liquid or lyophilized formulationof the invention, in one or more containers, and one or more otherprophylactic or therapeutic agents (e.g., cetirizine in combination withan additional active agent such as fluticasone, oxymetazoline ornaphazoline) useful for the treatment of allergic conjunctivitis and/orallergic rhinoconjunctivitis. The one or more other prophylactic ortherapeutic agents may be in the same container as the cetirizine or inone or more other containers. Preferably, the cetirizine is formulatedat a concentration of from about 0.05% (w/v) to about 1.0% (w/v) and issuitable for topical ocular administration. In certain embodiments,cetirizine is formulated with an additional active agents such asfluticasone, oxymetazoline or naphazoline, as described herein. Incertain embodiments, the kit contains the cetirizine in unit dosageform.

In certain embodiments, the kit further comprises instructions for usein the treatment of allergic conjunctivitis and/or allergicrhinoconjunctivitis (e.g., using the cetirizine formulations of theinvention alone or in combination with another prophylactic ortherapeutic agent), as well as side effects and dosage information forone or more routes of administration. Optionally associated with suchcontainer(s) is a notice in the form prescribed by a governmental agencyregulating the manufacture, use or sale of pharmaceuticals or biologicalproducts, which notice reflects approval by the agency of manufacture,use or sale for human administration. While the instructional materialstypically comprise written or printed materials they are not limited tosuch. Any medium capable of storing such instructions and communicatingthem to an end user is contemplated by this invention. Such mediainclude, but are not limited to electronic storage media (e.g., magneticdiscs, tapes, cartridges, chips), optical media (e.g. CD ROM), and thelike. Such media may include addresses to internet sites that providesuch instructional materials.

In another embodiment, this invention provides kits for the packagingand/or storage and/or use of the formulations described herein, as wellas kits for the practice of the methods described herein. The kits canbe designed to facilitate one or more aspects of shipping, use, andstorage.

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference.

EXAMPLES

The invention is further defined by reference to the following examples,which are not meant to limit the scope of the present invention. It willbe apparent to those skilled in the art that many modifications, both tothe materials and methods, may be practiced without departing from thepurpose and interest of the invention.

Example 1: Cetirizine (0.1%) Prevents Ocular Itching Associated withAllergic Conjunctivitis

A placebo controlled, double-blind study was conducted to evaluate theefficacy of cetirizine 0.1% (N=15) compared to vehicle (N=16). Subjectsunderwent 2 screening visits (an allergen titration and confirmation)followed by a drug evaluation visit. At the drug evaluation visit, onedrop of masked study medication was instilled in each eye and comfortassessments were taken. Sixteen hours later the subjects were challengedwith allergen and allergic assessments were taken. The results arepresented in Tables 1 and 2 and in FIGS. 1-2. The ocular itching scoreranges from 0, no itching, to 4, severe itching. The comfort scoreranges from 0, very comfortable, to 10, very uncomfortable (Note: Themost uncomfortable commercially available allergy drop=4). The resultsdemonstrate that a single drop of cetirizine (0.1%) ophthalmic solution(q.d.) was effective to prevent ocular itching associated with allergicconjunctivitis when administered 16 hours prior to conjunctival allergenchallenge (CAC), but had little effect on reducing conjunctival redness(FIGS. 1A and 1B). Differences between cetirizine and vehicle groupswere both clinically (≥1 unit difference) and statistically significant(P<0.05). In addition, as shown in Table 2, and FIG. 2, the cetirizineformulation was comfortable (i.e., well-tolerated) by the subjects.

TABLE 1 Mean Ocular Itching Scores (0-4 scale) following CAC 16 hrsafter dosing Mean Difference Time- Cetirizine 0.1% Vehicle (cetirizine-p- Statistic point HCl (N = 15) (N = 16) vehicle) value Mean Pre- 0.000.00 0.00 1.0000 (SD) CAC (0.00) (0.00) 3 min 1.67 2.36 −0.69 0.0191(1.12) (0.58) 5 min 1.52 2.56 −1.04 0.0051 (1.12) (0.60) 7 min 1.45 2.47−1.02 0.0031 (1.02) (0.72)

TABLE 2 Mean Drop Comfort Scores (0-10 scale) Cetirizine Mean DifferenceTime- 0.1% HCl Vehicle (cetirizine- p- Statistic point (N = 15) (N = 16)vehicle) value Mean Upon 0.47 0.72 −0.25 0.3908 (SD) Instillation (0.68)(1.49) 1 min 0.37 0.84 −0.47 0.1572 (0.49) (1.80) 2 min 0.47 0.81 −0.340.2467 (0.63) (1.53) 5 min 0.20 0.13 0.07 0.5981 (0.41) (0.34) 10 min0.27 0.31 −0.04 0.7864 (0.46) (0.70)

Example 2: Fluticasone Prevents Ocular and Nasal Symptoms Associatedwith Allergic Conjunctivitis

A placebo controlled, double-blind study was conducted to evaluate theefficacy of Fluticasone 0.001% (N=16), Fluticasone 0.005% (N=16),Fluticasone 0.01% (N=15) compared to vehicle alone (N=15). Subjectsunderwent 2 screening visits (allergen titration and confirmation)followed by 2 drug evaluation visits, as indicated in the study designshown in FIGS. 3A and 3B. At the drug evaluation visits, one drop ofmasked study medication was instilled in each eye and ocular allergicassessments were taken. Eight hours later the subjects were challengedwith allergen and primary and secondary ocular and nasal endpoints wereassessed, as well as safety of the formulations. The results arepresented in FIGS. 4-23.

Primary Ocular Endpoints

Ocular itching, conjunctival redness, lid swelling, and nasal congestionwere assessed in each subject during visit 4B.

Ocular itching was subjectively assessed on a scale of 0 (no itching) to4 (severe itching). As shown in FIG. 4, Fluticasone 0.001%, 0.005% and0.01% were about equally effective in reducing ocular itching over a 7minute time period as compared to vehicle alone.

Conjunctival redness was also subjectively assessed on a scale of 0 (noredness) to 4 (severe redness). As shown in FIG. 5, Fluticasone 0.001%,0.005% and 0.01% were about equally effective in reducing conjunctivalredness over a 20 minute period as compared to vehicle alone.

Lid swelling was subjectively assessed on a scale of 0 (no lid swelling)to 3 (severe lid swelling). As shown in FIG. 6, Fluticasone 0.001% and0.005% were each more effective than Fluticasone 0.01% at reducing lidswelling over a 20 minute period as compared to vehicle alone.

Nasal Congestion was subjectively assessed on a scale of 0 (nocongestion) to 4 (severe congestion). As shown in FIG. 7, Fluticasone0.001%, 0.005% and 0.01% were about equally effective in reducing nasalcongestion over a 30 minute period as compared to vehicle alone.

A summary of the results of the primary ocular endpoint assessments isshown in FIG. 8. As shown in FIG. 8, the reduction in conjunctivalredness by Fluticasone 0.005% and 0.01% and the reduction in lidswelling by Fluticasone 0.001% were each statistically significant(p<0.05).

Secondary Ocular Endpoints

Ciliary Redness, episcleral redness, chemosis and watery eyes wereassessed in each subject at visit 4B.

Ciliary redness was assessed on a scale of 0 (no redness) to 4 (severeredness). As shown in FIG. 9, Fluticasone 0.001%, 0.005% and 0.01% wereeach significantly effective in reducing ciliary redness over a 20minute period as compared to vehicle alone (p<0.05 for each Fluticasoneconcentration).

Episcleral redness was assessed on a scale of 0 (no redness) to 4(severe redness). As shown in FIG. 10, Fluticasone 0.001%, 0.005% and0.01% each reduce episcleral redness over a 20 minute period as comparedto vehicle alone.

Chemosis was assessed on a scale of 0 (none) to 4 (extreme). As shown inFIG. 11, Fluticasone 0.001%, 0.005% and 0.01% were each significantlyeffective in reducing chemosis over a 20 minute period.

Watery eyes were also subjectively assessed on a scale of 0 (not watery)to 4 (extremely watery). As shown in FIG. 12, Fluticasone 0.001% and0.05% were each more effective than Fluticasone 0.01% in reducing wateryeyes over a 20 minute period, as compared to vehicle alone.

A summary of the secondary ocular endpoints assessed is shown in FIG.13. As shown in FIG. 13, the reduction in ciliary redness by all threeconcentrations of Fluticasone, the reduction in episcleral redness byFluticasone 0.005%, and the reduction of watery eyes by Fluticasone0.05% were each statistically significant (p<0.05).

Secondary Nasal Endpoints

Rhinorrhea, ear or palate pruritis, nasal pruritis were assessed in eachsubject at visit 4B using a scale of 0 (none) to 4 (extreme) for eachendpoint.

As shown in FIGS. 14 and 16, Fluticasone 0.001%, 0.005% and 0.01% eachhad a clinically significant effect in reducing rhinorrhea and nasalpruritis, respectively, over a 20 minute period as compared to vehiclealone. Shown in FIG. 15, Fluticasone 0.001%, 0.005% and 0.01% were eachhad an effect in reducing ear and palate pruritis as compared to vehiclealone.

Total nasal scores were assessed on a scale of 0-16. As shown in FIG.17, Fluticasone 0.001%, 0.005% and 0.01%, each surprisingly had aclinically significant effect on total nasal score when administereddirectly to the eye of each subject. A summary of the nasal endpointsassessed is shown in FIGS. 18 and 19.

Safety

Intraocular pressure, drop comfort and adverse events such as blurryvision, conjunctival hemorrhage, dry eye, site pain and/or irritationand headache, were assessed for each subject.

Drop comfort was subjectively assessed on a scale of 0 (extremelycomfortable) to 10 (extremely uncomfortable) during visit 2 and visit 3.As shown in FIGS. 20 and 21, Fluticasone 0.01 was highly uncomfortableupon instillation as compared to Fluticasone 0.001% and 0.005%, and ascompared to vehicle alone. The comfort of Fluticasone 0.001% and 0.005%were comparable to the comfort of the vehicle control.

A summary of the total percentage of subjects who experienced adverseevents such as blurry vision, conjunctival hemorrhage, dry eye, sitepain and/or irritation, and headache, is shown in FIG. 22.

The effect of each concentration of Fluticasone on intraocular pressure(TOP) as compared to vehicle alone is shown in FIG. 23.

The results demonstrate that a single drop of either Fluticasone 0.001%,0.005% or 0.01% was effective to prevent both ocular and nasal symptomsassociated with allergic conjunctivitis. However, when taking allprimary and secondary endpoints into consideration, Fluticasone 0.005%was the most efficacious in relieving both ocular and nasal symptoms,and was shown to be more comfortable than Fluticasone 0.001% andFluticasone 0.01%, with no adverse effect on intraocular pressure.

Example 3: An Evaluation of the Effects of TopicalCetirizine/Fluticasone Ophthalmic Formulations on the Signs of AllergicConjunctivitis Using the Murine Model of Ragweed-Induced ActiveAnaphylaxis

Seasonal allergic conjunctivitis (hay fever conjunctivitis) develops ina subset of atopic individuals (those with a genetic disposition ofhypersensitivity to allergens). The signs and symptoms of the conditionare elicited by airborne allergens (e.g. ragweed, tree and grasspollens, animal dander). Seasonal allergic conjunctivitis is the mostcommon form of ocular allergic disease and may account for up to 90% ofallergic disorders seen.

The most common and distressing ocular signs and symptoms associatedwith allergic conjunctivitis are itching and redness. Swelling, mucousdischarge and excessive tearing are frequently involved. In allergicconjunctivitis, airborne allergens presumably dissolve in the tear film,traverse the conjunctiva, and then bind with IgE antibodies attached tothe surface of the conjunctival mast cell to trigger an allergicresponse. This attachment results in mast cell degranulation and releaseof chemical mediators that lead to signs and symptoms of allergicdisease. Some of these substances, e.g. histamines and prostaglandins,directly affect blood vessels and nerves, whereas others influence themigration of inflammatory cells such as neutrophils, eosinophils andmacrophages, causing inflammation.

The major chemical mediator involved in producing ocular symptoms ishistamine. Several types of histamine have been identified in the humanconjunctiva. Stimulation of H1 receptors results mainly in itching whilestimulation of H2 receptors results largely in vasodilation (redness).However, studies with antihistamines known to be highly specific for H1receptors have suggested that H1 receptors may also have a secondaryeffect on redness.

The purpose of this study was to investigate the potential ofcetirizine/fluticasone combination formulations in preventing signs ofallergic conjunctivitis in a murine active anaphylaxis model. In thismodel, mice are systemically sensitized to short ragweed allergen (SRW)and then challenged by instilling SRW in the eyes. Therapeutic treatmentis given after sensitization but prior to topical challenge. Allergenspresent in the SRW preparation cross-link IgE antibodies bound toconjunctival mast cells causing degranulation and release of histamineand other allergic mediators, which in turn produce the characteristicsigns and symptoms of allergic conjunctivitis.

Four test formulations, containing combination 0.1% Cetirizine/0.005%Fluticasone (“low dose”), combination 0.25% Cetirizine/0.01% Fluticasone(“high dose”), 0.1% Cetirizine or 0.005% Fluticasone, were compared withvehicle alone (1% Polyethylene Glycol 400, NF; 0.2% Dibasic SodiumPhosphate, Anhydrous, USP; 0.25% Hypromellose, USP; 0.1% Polysorbate 80,NF; 1.8% Glycerin, USP; 0.025% Edetate Disodium, USP; 0.01% BenzalkoniumChloride, NF (pH 7.0)) and two commercial positive controls, Pred Forte®(prednisolone acetate 1%) and Pataday® (olopatadine 0.2%).

Systemic sensitization to short ragweed allergen (SRW) was induced byinjecting SRW plus alum adjuvant systemically into Balb/c mice (Day 1),and by administration of topical SRW eyedrops on days 19-21. Topicalocular drug treatment was administered daily on days 19-21 after SRWinjection. After 3 days of treatment, the animals were assessed forsigns of allergic conjunctivitis in response to challenge with topicalSRW administration. Clinical assessments included conjunctivalhyperemia, chemosis, discharge and lid swelling, each gradedbiomicroscopically on a 0-4 severity scale.

After 3 days of drug treatment, the animals treated with the combination0.1% Cetirizine/0.005% Fluticasone demonstrated the least severity inthree clinical signs (conjunctival hyperemia, chemosis, and lidswelling) as compared Cetirizine or Fluticasone alone or as compared tomost other treatment groups. Cetirizine or Fluticasone alone produced nosignificant treatment effects.

The reduction in clinical signs in response to SRW challenge after 3days of treatment with the combination 0.1% Cetirizine/0.005%Fluticasone was statistically significantly lower than Fluticasone alonefor hyperemia (p≤0.001), chemosis (p≤0.01), lid swelling (p≤0.03) andtotal clinical score (p≤0.01); and than Cetirizine alone for chemosis(p≤0.05). Borderline Additionally, statistical significance was almostachieved against Cetirizine alone for total clinical score (p=0.06).Surprisingly, the reduction with the combination was more than couldhave been expected from the efficacy of the individual components.

Furthermore, the combination of 0.1% Cetirizine/0.005% Fluticasoneperformed better than either the steroid (Pred Forte®) or antihistamine(Pataday®), commercial products used as positive controls in this study.Additionally, the higher concentration of the combination (0.25%Cetirizine/0.01% Fluticasone) was minimally effective in this modelunder this dosing regimen and conditions.

The results of this study indicate that a substantial clinical benefitmay be achieved with the combination of low dose Cetirizine/Fluticasoneover its individual components, over the high dose combination and overexisting lead commercial products.

Experimental Design:

TABLE 3 Schedule of Procedures Day Day Day Day Day Procedure 0 19 20 2126 Ocular Exam X X SRW Injection X Topical SRW X X X Dosing X X XChallenge X Behavior X Observations Photographs X Euthanasia X Eye XEnucleations

Sensitization

On Day 0, animals received injections containing a suspension of 50 μgof short ragweed allergen (SRW, Greer, Lenoir, N.C., USA) in 25 μL alum(aluminum hydroxide gel). Additional sensitization was achieved bytopical dosing with 1 mg SRW in 5 μl PBS on Days 19 and 20 afterinjection.

Dosing

On days 19 through 21, topical treatment was administered once daily.Mice were dosed topically to the central cornea using a calibratedmicropipette, with a 5 μL drop of treatment in each eye. The dose groupsare outlined in the table below:

Challenge

On day 21, twenty minutes after ocular treatment dosing, animals werechallenged with topical doses of 1000 μg SRW suspension in 5 μl PBS ineach eye. SRW was prepared fresh and used within 3 hours of mixing, andmixed well before administration to ensure homogeneity.

TABLE 4 Test/Control Articles Group Number of Volume per Number AnimalsTest Article Dose 1 8 0.1% Cetirizine/0.005% 5 μL Fluticasone 2 8 0.25%Cetirizine/0.01% 5 μL Fluticasone 3 8 0.1% Cetirizine 5 μL 4 8 0.005%Fluticasone 5 μL 5 8 Olopatadine HCl 0.2% 5 μL (Pataday ®) 6 8 Pred.acetate 1% 5 μL (Pred Forte ®) 7 8 Vehicle Control 5 μL

Experimental Procedures:

Ophthalmic exams were performed at baseline (study entry) according tothe Ocular Irritation Grading Scale (Appendix 1) to verify that the eyesdid not exhibit any signs of ocular irritation.

Ophthalmic exams were also performed on day 21, 15 minutes after theallergen challenge. Exams were performed under dissecting microscope,and included conjunctival hyperemia, chemoosis, tear/discharge, and lidswelling, each graded on a 0-4 scale (0.5 units were allowed for anyocular score).

There were no abnormal ophthalmic findings in any animals used in thestudy and no unscheduled deaths during this study.

Tissue Collections/Preservation and Statistical Analysis

Immediately after euthanasia (CO₂ inhalation and cervical dislocation),eyes and surrounding lid tissue was collected and placed immediately in4% paraformaldehyde for 24 hours, after which they were transferred to70% ethanol for storage prior to paraffin embedding and sectioning forhistology.

Both eyes of each animal were averaged and all animals within a groupwere averaged to obtain an average score for each treatment group foreach measurement parameter. Statistically significant differencesbetween groups were determined using the 2-tailed, 2-sample t-test.

Results

Day 0 baseline exams ensured that all mice were free of any redness,swelling, and tearing.

After 3 days of drug treatment, the animals treated with the combination0.1% Cetirizine/0.005% Fluticasone demonstrated the least severity inthree of the four clinical signs (conjunctival hyperemia, chemosis, andlid swelling) as compared to Cetrizine or Fluticasone alone, and ascompared to most other treatment groups. Total clinical score (sum ofscores of all clinical signs in both eyes) was lowest in the 0.1%Cetirizine/0.005% Fluticasone combination group as compared to all othertreatment groups. Cetirizine or Fluticasone alone produced nosignificant treatment effects.

The reduction in clinical signs in response to SRW challenge after 3days of treatment with the combination 0.1% Cetirizine/0.005%Fluticasone was statistically significantly lower than Fluticasone alonefor hyperemia (p≤0.001), chemosis (p≤0.01), lid swelling (p≤0.03) andtotal clinical score (p≤0.01); and than Cetirizine alone for chemosis(p≤0.05). Borderline significance was achieved against Cetirizine alonefor total clinical score (p=0.06).

Surprisingly, the high dose combination of 0.25% Cetirizine/0.01%Fluticasone was less effective than the low dose combination in thismodel for all clinical signs, with the exception of an effect onchemosis. The only statistically significant decrease in any clinicalsign after high dose combination treatment was for chemosis as comparedto Fluticasone alone (p≤0.05).

Under these treatment conditions (3 days of once-daily dosing), neitherof the positive control test articles, commercially available Pred Forte(prednisolone acetate 1%), a steroid, or Pataday (olopatadine 0.2%), theleading anti-histamine, produced significant treatment effects, with theexception of a decrease in chemosis produced by olopatadine, comparableto the effect seen with the combination 0.1% Cetirizine/0.005%Fluticasone. This chemosis effect was statistically significantlydifferent from Fluticasone alone (p≤0.05).

The results are summarized in Table 5 below and in FIGS. 24-28.

TABLE 5 Summary of Results Conjunctival Total Clinical HyperemiaChemosis Discharge Lid Edema Score Treatment Group Average SEM Avg SEMAvg SEM Avg SEM Avg SEM 0.1% Cetirizine/ 1.00 0.11 1.22 0.11 1.38 0.121.56 0.09 10.31 0.66 0.005% Fluticasone 0.25% Cetirizine/ 1.53 0.14 1.280.15 1.41 0.18 1.69 0.27 11.63 1.09 0.01% Fluticasone 0.1% Cetirizine1.34 0.17 1.59 0.14 1.66 0.21 1.78 0.15 12.75 1.00 0.005% Fluticasone1.78 0.15 1.66 0.09 1.34 0.15 1.97 0.14 13.50 0.80 Olopatadine HCl 1.470.25 1.19 0.19 1.53 0.15 1.63 0.16 11.63 1.34 0.2% (Pataday ®) Pred.acetate 1% 1.61 0.14 1.50 0.12 1.79 0.26 1.93 0.28 12.86 1.43 (PredForte ®) Vehicle Control 1.53 0.20 1.38 0.13 1.56 0.24 1.94 0.18 12.811.19

CONCLUSION

The low dose combination of 0.1% Cetirizine/0.005% Fluticasone was themost effective at preventing signs of allergic conjunctivitis in themurine ragweed sensitization model. Neither component of the combinationused alone, at the same concentrations, produced a substantial treatmenteffect. The low-dose combination, assessed after 3 days of treatment and15 minutes after ragweed challenge, reduced conjunctival hyperemia,chemosis, and lid swelling, and resulted in the lowest clinical summaryscore of any of the treatment arms, including the cetirizine orfluticasone alone, and commercial ophthalmics Pataday® and Pred Forte®.

Surprisingly, the higher concentration of the combination (0.25%Cetirizine/0.01% Fluticasone) was minimally effective in this modelunder this dosing regimen and conditions. These results indicate thatthe 0.1% Cetirizine/0.005% Fluticasone formulation has excellentpotential for the prevention and treatment of allergic conjunctivitisand that a substantial clinical benefit might be achieved with thecombination of Cetirizine/Fluticasone over either medication used alone.

In summary, the results consistently favored 0.1% cetirizine/0.005%fluticasone combination (low dose) over both the individual componentsalone as well as the high dose combination (0.25% cetirizine/0.01%fluticasone), which is surprising because one skilled in the art mightexpect the higher dose formulation to work at least equally well if notbetter than the low dose formulation. The low dose combination alsoworked better than would be expected from the results of the individualcomponents, thus showed a synergistic effect between the cetirizine andfluticasone

Additionally, the low dose combination worked better than well known,leading ocular antihistamines and ocular steroids—these results confirmthe effectiveness of the specific combination of cetirizine/fluticasoneat the preferred low dose concentrations.

Lastly, the low dose combination was more efficacious than itscomparison arms across all endpoints, including total ocular compositescore.

Example 4: Comfort Profile of Cetirizine/Fluticasone Formulation

The purpose of this study was to assess the comfort of a 0.1%cetirizine/0.005% fluticasone (low dose) formulation and a 0.25%cetirizine/0.01% fluticasone (high dose) formulation upon instillationin the human eye (N=5). The low dose and high dose combinations wereeach formulated in 1% Polyethylene Glycol 400, NF; 0.2% Dibasic SodiumPhosphate, Anhydrous, USP; 0.25% Hypromellose, USP; 0.1% Polysorbate 80,NF; 1.8% Glycerin, USP; 0.025% Edetate Disodium, USP; 0.01% BenzalkoniumChloride, NF, as reflected in Tables 6 and 6 below:

TABLE 6 0.005% Fluticasone Propionate/0.1% Cetirizine OphthalmicSuspension Concentration Ingredient Purpose  0.005% FluticasonePropionate, USP Active, Steroid    1% Polyethylene Glycol 400, NFCarrier   0.2% Dibasic Sodium Phosphate, Buffer Anhydrous, USP 0.1188%Cetirizine Dihydrochloride, Active, Ph.Eur. Antihistamine  0.25%Hypromellose, USP Viscosity agent   0.1% Polysorbate 80, NF Surfactant  1.8% Glycerin, USP Tonicity Agent  0.025% Edetate Disodium, USPChelating Agent  0.01% Benzalkonium Chloride, N.F. Preservative q.s.Sterile Purified Water Vehicle

TABLE 7 0.01% Fluticasone Propionate/0.25% Cetirizine OphthalmicSuspension Concentration Ingredient Purpose  0.01% FluticasonePropionate, USP Active, Steroid   2% Polyethylene Glycol 400, NF Carrier 0.2% Dibasic Sodium Phosphate, Buffer Anhydrous, USP 0.297% CetirizineDihydrochloride, Active, Ph.Eur. Antihistamine  0.25% Hypromellose, USPViscosity agent  0.1% Polysorbate 80, NF Surfactant  1.2% Glycerin, USPTonicity Agent 0.025% Edetate Disodium, USP Chelating Agent  0.01%Benzalkonium Chloride, N.F. Preservative q.s. Sterile Purified WaterVehicle

Each of the formulations in Tables 5 and 6 had a pH 7.0 and anosmolality of 300 mOsm/kg.

One drop of masked study medication was instilled in each eye andsubjects were asked to assess the comfort of the drop on a subjectivescale of 0 to 10 (0=comfortable, 10=very uncomfortable (Note: The mostuncomfortable commercially available allergy drop=4). The results areshown in FIG. 29. Both the low dose and high dose formulations were welltolerated (average comfort score <3) and were found to be morecomfortable than the formulation comprising 0.005% fluticasone alone asthe only active agent, which had an osmolality of 900 mOsm/kg (averagecomfort score ˜3; See FIGS. 20-21, Example 2).

Example 5: Clinical Efficacy of Cetirizine/Fluticasone Formulations

A placebo controlled, double-blind study will be conducted to evaluatethe efficacy of cetirizine 0.1%/fluticasone 0.005% formulation (lowdose) formulation compared to the individual treatment arms (i.e.,cetirizine alone and fluticasone alone) and a vehicle control.

Subjects will undergo 2 screening visits (an allergen titration andconfirmation) followed by a drug evaluation visit. At the drugevaluation visit, one drop of masked study medication will be instilledin both eyes and comfort assessments will be taken. Sixteen hours latersubjects will be challenged with allergen (conjunctival allergenchallenge; “CAC”) and allergic assessments will be taken. Subjects willbe asked to subjectively rate their ocular itching on a scale of 0 to 4(0=little to no itching, 4=extreme itching). Conjunctival redness(post-CAC) will also be evaluated. Subjects will be further asked tokeep a diary to evaluate ocular itching and conjunctival redness over a2 week period. Intraocular pressure (“TOP”) measurements and any adverseevents will be measured/collected over 14 days dosing.

Based on the surprising results of the in vivo animal study described inExample 3 above, it is anticipated that the low dosecetirizine/fluticasone formulation will be more efficacious than boththe individual components (i.e., cetirizine alone and fluticasone alone)and the vehicle control in reducing ocular itching and conjunctivalredness (post-CAC). Based on the clinical efficacy of the 0.1%cetirizine alone formulation (see Example 1), it is anticipated that thelow 0.1% cetirizine/0.005% fluticasone formulation will be even moreefficacious in reducing the signs and symptoms of allergicconjunctivitis for at least 16 hours or more, as compared to thecetirizine alone, and will have better efficacy at treating the latephase allergic inflammation response.

Example 6: Stability of 0.10% Cetirizine Formulation and CombinedCetirizine/Fluticasone Formulations

Tables 8-9 below show that a 0.1% formulation of cetirizine was stablefor at least three months both at room temperature (Table 6) and athigher temperatures (Table 7).

Tables 10-11 below show that a 0.1% cetirizine/0.005% fluticasoneformulation (in 1% Polyethylene Glycol 400, NF; 0.2% Dibasic SodiumPhosphate, Anhydrous, USP; 0.25% Hypromellose, USP; 0.1% Polysorbate 80,NF; 1.8% Glycerin, USP; 0.025% Edetate Disodium, USP; 0.01% BenzalkoniumChloride, NF (pH 7.0); i.e., the formulation listed in Table 5) wasstable for at least one month at both room temperature (Table 8) and athigher temperature (Table 9) when stored upright.

Tables 12 and 13 show that a 0.25% cetirizine/0.01% fluticasoneformulation (in 1% Polyethylene Glycol 400, NF; 0.2% Dibasic SodiumPhosphate, Anhydrous, USP; 0.25% Hypromellose, USP; 0.1% Polysorbate 80,NF; 1.8% Glycerin, USP; 0.025% Edetate Disodium, USP; 0.01% BenzalkoniumChloride, NF (pH 7.0); i.e., the formulation listed in Table 6) wasstable for at least one month at room temperature (Table 10) and at ahigher temperature (Table 11) when stored upright.

Cetirizine and fluticasone concentrations were quantified by highpressure liquid chromatography (HPLC). Impurities are shown as “relativeretention time” or RRT in the table, which relates the unknown peak tothe elution time of the parent peak, cetirizine (or fluticasone). At notime did the total impurities exceed 1%. Sterility, particulate matter,and preservative efficacy were determined only at the initial time pointbecause these should remain unchanged provided that the sealed containeris not compromised.

The data herein demonstrates cetirizine and cetirizine/fluticasoneformulations that are stable without the inclusion of a cyclodextrin orother solubilizing compound. Without intending to be bound by anytheory, the stability was achieved by minimizing/excluding the additionof counter ions or metal based buffers that could promote saltformation, precipitation, or metal based degradation.

TABLE 8 Cetirizine 0.10%/Benzalkonium Chloride 0.01% (w/v) OphthalmicSolution Stability Testing: 25° C./60% RH (QA Oct. 13, 2008) Lot #:04262008@18 Initial 1 Month 2 Month 3 Month Test Limits/SpecificationJun. 9, 2008 Jul. 9, 2008 Aug. 11, 2008 Sep. 10, 2008 Appearance Clearand colorless to Conforms: Clear, Conforms: Clear, Conforms: Clear,Conforms: Clear, (Contents) slightly yellow solution Colorless SolutionColorless Solution Colorless Solution Colorless Solution Appearance Noleakage observed, Conforms: No leakage, Conforms: No leakage, Conforms:No leakage, Conforms: Noleakage, (Container Integrity) container intactcontainer intact container intact container intact container intactAssay: Cetirizine NLT 90.0% and NMT 99.2% LC 99.5% LC 99.7% LC 99.4% LCLabel Claim: 0.10% 110.0% of Label Claim (LC) (w/v) (equivalent toCetirizine dihydrochloride 0.1188%) Assay of Ketotifen Absence of ActiveNot Detected Not Detected Not Detected Not Detected Impurities (Total,Report individual ≥0.05% RRT @ 0.93: 0.06% RRT @ 0.90: 0.06% RRT @ 0.67:0.07% RRT @ 0.63: 0.09% Ketotifen impurities, Report Total  RRT @ 1.1:0.15% RRT @ 1.60: 0.06% RRT @ 0.91: 0.06% RRT @ 0.92: 0.05% Cetirizineimpurities) Total: 0.2% RRT @ 2.33: 0.06% RRT @ 1.10: 0.05% RRT @ 1.08:0.05% Total: 0.2% RRT @ 1.11: 0.09% RRT @ 1.10: 0.09% RRT @ 2.33: 0.06%RRT @ 1.56: 0.08% Total: 0.30%% Total: 0.40%% Assay: Benzalkonium NLT85.0% and NMT 99.4% LC 94.6% LC 100.0% LC 94.7% LC Chloride 115% ofLabel Claim Label Claim: 0.01% (w/v) pH 5.5 ± 0.5 5.7 6.0 6.0 5.9Osmolality Report 253 mOsm/Kg · H₂0 253 mOsm/Kg · H₂0 253 mOsm/Kg · H₂0252 mOsm/Kg · H₂0 Sterility Meets USP Criteria Pass Particulate MatterNumber of particles with Pass diameter of:  ≥10 μm: NMT 50/mL ≥25 μm:NMT 5/mL ≥50 μm: NMT 2/mL Antimicrobial Report Pass PreservativeEfficacy

TABLE 9 Cetirizine 0.10%/Benzalkonium Chloride 0.01% (w/v) OphthalmicSolution Stability Testing: 40° C./75% RH (QA Oct. 13, 2008) (Lot #:04262008@18) Initial 1 Month 2 Month 3 Month Test Limits/SpecificationJun. 9, 2008 Jul. 9, 2008 Aug. 11, 2008 Sep. 10, 2008 Appearance Clearand colorless to Conforms: Clear, Conforms: Clear, Conforms: Clear,Conforms: Clear, (Contents) slightly yellow solution Colorless SolutionColorless Solution Colorless Solution Colorless Solution Appearance Noleakage observed, Conforms: No leakage, Conforms: No Conforms: NoConforms: No (Container Integrity) container intact container intactleakage, container leakage, container leakage, container intact intactintact Assay: Cetirizine NLT 90.0% and NMT 99.2% LC 99.6% LC 100.1% LC99.4% LC Label Claim: 0.10% 110.0% of Label Claim (w/v) (equivalent to(LC) Cetirizine dihydrochloride 0.1188%) Assay of Ketotifen Absence ofActive Not Detected Not Detected Not Detected Not Detected Impurities(Total, Report individual ≥0.05% RRT @ 0.93: 0.06% RRT @ 0.90: 0.06% RRT@ 0.67: 0.34% RRT @ 0.63: 0.44% Ketotifen impurities, Report Total  RRT@ 1.1: 0.15% RRT @ 2.11: 0.06% RRT @ 0.78: 0.05% RRT @ 0.92: 0.05%Cetirizine impurities) Total: 0.2% Total: 0.1% RRT @ 0.91: 0.06% RRT @1.10: 0.09% RRT @ 1.10: 0.05% Total: 0.6% RRT @ 1.11: 0.09% RRT @ 2.33:0.06% Total: 0.70%% Assay: Benzalkonium NLT 85.0% and NMT 99.4% LC 92.9%LC 99.1% LC 96.8% LC Chloride 115% of Label Claim Label Claim: 0.01%(w/v) pH 5.5 ± 0.5 5.7 6.0 5.9 5.7 Osmolality Report 253 mOsm/Kg.H₂0 254mOsm/Kg.H₂0 254 mOsm/Kg.H₂0 255 mOsm/Kg.H₂0 Sterility Meets USP CriteriaPass Particulate Matter Number of particles with Pass diameter of:  ≥10μm: NMT 50/mL ≥25 μm: NMT 5/mL ≥50 μm: NMT 2/mL Antimicrobial ReportPass Preservative Efficacy

TABLE 10 0.005% Fluticasone Propionate/0.1% Cetirizine OphthalmicSuspension Stability Testing: 25° C./40% RH (Lot Number: Ora091202.V1)Test Initial 1 Week 2 Week 2 Week 1 Month Date Pulled Dec. 15, 2009 Dec.21, 2009 Dec. 28, 2009 Jan. 4, 2010 Jan. 13, 2010 Inverted InvertedInverted Upright Upright Specification Orientation OrientationOrientation Orientation Orientation Appearance Report Results Clear,Colorless, Clear, Colorless, Clear, Colorless, NT Slightly Turbid(Solution) no ppt. no ppt. no ppt. Solution Appearance No leakage NT Noleakage No leakage NT No leakage (Container) observed, observed,observed, observed, container intact container intact container intactcontainer intact Fluticasone 90%-110% Label 95.1% LC 98.6% LC  89.4% LC*102.4% LC 99.6% LC Propionate Assay Claim Fluticasone Related Reportindividual RRT 0.19: RRT 0.19: RRT 0.09: RRT 0.07: RRT 0.12: Substances% AUC, 0.75% AUC 0.50% AUC 0.06% AUC 0.25% AUC 0.39% AUC Report total, %AUC RRT 0.36: RRT 0.36: RRT 0.10: RRT 0.09: RRT 0.14: 0.35% AUC 0.40%AUC 0.14% AUC 0.06% AUC 0.63% AUC Total: 1.07% AUC RRT 0.66: RRT 0.12:RRT 0.10: RRT 0.29: 0.24% AUC 0.72% AUC 0.16% AUC 0.41% AUC RRT 0.93:RRT 0.27: RRT 0.12: RRT 0.34: 0.07% AUC 0.49% AUC 0.53% AUC 0.10% AUCTotal: 1.21% RRT 0.33: RRT 0.27: Total: 1.53% AUC 0.18% AUC 0.46% AUCRRT 0.52: RRT 0.33: 0.05% AUC 0.14% AUC RRT 0.61: Total: 1.6% 0.29% AUCRRT 0.76: 0.23% AUC RRT 0.88: 0.27% AUC Total: 2.43% Cetirizine Assay90%-110% Label 98.6% LC 97.2% LC 98.0% LC NT 96.5% LC Claim CetirizineRelated Report individual RRT 0.96: RRT 0.96: RRT 0.96: NT RRT 1.13:Substances % AUC, 0.5% AUC 0.05% AUC 0.05% AUC 0.53% AUC Report total, %AUC RRT 1.13: RRT 1.13: RRT 1.13: Total: 0.53% AUC 0.08% AUC 0.18% AUC0.19% AUC Total: 0.13% Total: 0.23% Total: 0.24% Benzalkonium 50%-150%Label 99.5% LC NT NT NT 101.0% LC  chloride Assay Claim Disodium Edetate70%-120% Label 95.8% LC NT NT NT 91.2% LC Claim pH 6.5-7.8 7.1 7.0 7.0NT 7.0 Osmolality Report results 291 mOsm/Kg 290 mOsm/Kg 291 mOsm/Kg NT290 mOsm/Kg RH = relative humidity, LC = label claim, AUC = area undercurve, NT = not tested. *The low assay values were attributed to theinverted orientation in which the stability samples were stored. Samplesstored in the upright orientation were tested at the 2-week time pointand subsequent time points, as reflected in the data shown.

TABLE 11 0.005% Fluticasone Propionate/0.1% Cetirizine OphthalmicSuspension Stability Testing: 40° C./NMT 25% RH (Lot Number:Ora091202.V1) Test Initial 1 Week 2 Week 2 Week 1 Month Date Pulled Dec.15, 2009 Dec. 21, 2009 Dec. 28, 2009 Jan. 4, 2010 Jan. 13, 2010 InvertedInverted Inverted Upright Upright Specification Orientation OrientationOrientation Orientation Orientation Appearance Report Results Clear,Colorless, Clear, Colorless, Clear, Colorless, NT Slightly turbid(Solution) no ppt. no ppt. no ppt. solution Appearance No leakage NT Noleakage No leakage NT No leakage (Container) observed, observed,observed, observed, container intact Container intact Container intactcontainer intact Fluticasone 90%-110% Label 95.1% LC  82.2% LC* 58.4%LC* 103.2% LC 101.4% LC  Propionate Assay Claim Fluticasone RelatedReport individual RRT 0.19: RRT 0.19: RRT 0.09: RRT 0.07: RRT 0.11:Substances % AUC, 0.75% AUC 0.42% AUC 0.66% AUC 0.26% AUC 0.69% AUCReport total, % AUC RRT 0.36: RRT 0.36: RRT 0.10: RRT 0.09: RRT 0.14:0.35% AUC 0.48% AUC 0.59% AUC 0.52% AUC 0.59% AUC Total: 1.07% AUC RRT0.66: RRT 0.12: RRT 0.10: RRT 0.29: 0.32% AUC 0.72% AUC 0.13% AUC 0.35%AUC RRt 0.93: RRT 0.28: RRT 0.12: RRT 0.34: 0.18% AUC 0.72% AUC 0.35%AUC 0.60% AUC Total: 1.40% RRT 0.33: RRT 0.27: Total: 2.23% AUC 1.12%AUC 0.43% AUC RRT 0.45: RRT 0.33: 0.20% AUC 0.19% AUC RRT 0.49: RRT0.76: 0.11% AUC 0.06% AUC RRT 0.53: Total: 2.02% 0.14% AUC RRT 0.60:0.14% AUC RRT 0.76: 0.31% AUC RRT 0.88: 0.49% AUC Total: 5.20%Cetirizine Assay 90%-110% Label 98.6% LC 97.2% LC 97.9% LC NT 96.8% LCClaim Cetirizine Related Report individual RRT 0.96: RRT 1.13: RRT 1.13:NT RRT 1.13: Substances % AUC, 0.5% AUC 0.47% AUC 0.48% AUC 0.82% AUCReport total, % AUC RRT 1.13: Total: 0.47% Total: 0.48% Total: 0.82% AUC0.08% AUC Total: 0.13% Benzalkonium 50%-150% Label 99.5% LC NT NT NT101.3% LC  chloride Assay Claim Disodium Edetate 70%-120% Label 95.8% LCNT NT NT 91.0% LC Claim pH 6.5-7.8 7.1 7.0 7.0 NT 7.0 Osmolality Reportresults 291 mOsm/Kg 292 mOsm/Kg 293 mOsm/Kg NT 291 mOsm/Kg RH = relativehumidity, LC = label claim, AUC = area under curve, NT = not tested.*The low assay values were attributed to the inverted orientation inwhich the stability samples were stored. Samples stored in the uprightorientation were tested at the 2-week time point and subsequent timepoints, as reflected in the data shown.

TABLE 12 0.01% Fluticasone Propionate/0.25% Cetirizine OphthalmicSuspension Stability Testing: 25° C./40% RH (Lot Number: Ora091130.V1)Test Initial 1 Week 2 Week 2 Week 1 Month Date Pulled Dec. 15, 2009 Dec.21, 2009 Dec. 28, 2009 Jan. 4, 2010 Jan. 13, 2010 Inverted InvertedInverted Upright Upright Specification Orientation OrientationOrientation Orientation Orientation Appearance Report Results Clear,Colorless, Clear, colorless, Clear, colorless, NT Slightly turbid(Solution) no ppt. no ppt no ppt solution Appearance No leakage NT Noleakage No leakage NT No leakage (Container) observed, observed,observed, observed, container intact container intact container intactcontainer intact Fluticasone 90%-110% Label 96.9% LC 98.9% LC  79.0% LC*99.6% LC 99.2% LC Propionate Assay Claim Fluticasone Related Reportindividual RRT 0.18: RRT 0.19: RRT 0.06: RRT 0.06: RRT 0.11: Substances% AUC, 0.82% AUC 0.61% AUC 0.36% AUC 0.49% AUC 0.46% AUC Report total, %AUC RRT 0.35: RRT 0.35: RRT 0.09: RRT 0.09: RRT 0.13: 0.40% AUC 0.47%AUC 0.38% AUC 0.38% AUC 0.74% AUC Total: 1.22% RRT 0.67: RRT 0.12: RRT0.12: RRT 0.29: 0.43% AUC 0.82% AUC 0.66% AUC 0.50% AUC Total: 1.51% RRT0.27: RRT 0.27: Total: 1.17% AUC 0.67% AUC 0.53% AUC RRT 0.33: RRT 0.36:0.20% AUC 0.20% AUC RRT 0.44: RRT 0.52: 0.31% AUC 0.09% AUC RRT 0.51:Total: 2.35% 0.42% AUC RRT 0.60: 0.27% AUC RRT 0.76: 1.04% AUC RRT 0.88:1.48% AUC Total: 6.14% Cetirizine Assay 90%-110% Label 99.3% LC 97.3% LC98.7% LC NT 97.2% LC Claim Cetirizine Related Report individual RRT0.96: RRT 0.96: RRT 0.96: NT RRT 1.13: Substances % AUC, 0.05% AUC 0.05%AUC 0.05% AUC 0.75% AUC Report total, % AUC RRT 1.13: RRT 1.13: RRT1.13: Total: 0.75% AUC 0.14% AUC 0.31% AUC 0.32% AUC Total: 0.19% Total:0.36% Total: 0.37% Benzalkonium 50%-150% Label 96.7% LC NT NT NT 100.6%LC  chloride Assay Claim Disodium Edetate 70%-120% Label 92.9% LC NT NTNT 89.7% LC Claim pH 6.5-7.8 7.1 7.1 7.1 NT 7.1 Osmolality Reportresults 272 mOsm/Kg 273 mOsm/Kg 274 mosm/Kg NT 273 mOsm/Kg RH = relativehumidity, LC = label claim, AUC = area under curve, NT = not tested.*The low assay values were attributed to the inverted orientation inwhich the stability samples were stored. Samples stored in the uprightorientation were tested at the 2-week time point and subsequent timepoints, as reflected in the data shown.

TABLE 13 0.01% Fluticasone Propionate/0.25% Cetirizine OphthalmicSuspension Stability Testing: 40° C./NMT 25% RH (Lot Number:Ora091130.V1) Test Initial 1 Week 2 Week 2 Week 1 Month Date Pulled Dec.15, 2009 Dec. 21, 2009 Dec. 28, 2009 Jan. 4, 2010 Jan. 13, 2010 InvertedInverted Inverted Upright Upright Specification Orientation OrientationOrientation Orientation Orientation Appearance Report Results Clear,Colorless, Clear, colorless, Clear, colorless, NT Slightly turbid(Solution) no ppt. no ppt no ppt solution Appearance No leakage NT Noleakage No leakage NT No leakage (Container) observed, observed,observed, observed, container intact container intact container intactcontainer intact Fluticasone 90%-110% Label 96.9% LC 98.5% LC  51.4% LC*100.4% LC 98.9% LC Propionate Assay Claim Fluticasone Related Reportindividual RRT 0.18: RRT 0.19: RRT 0.09: RRT 0.06: RRT 0.11: Substances% AUC, 0.82% AUC 0.47% AUC 1.09% AUC 0.44% AUC 0.94% AUC Report total, %AUC RRT 0.35: RRT 0.35: RRT 0.10: RRT 0.09: RRT 0.13: 0.40% AUC 0.49%AUC 0.43% AUC 0.93% AUC 0.71% AUC Total: 1.22% RRT 0.66: RRT 0.12: RRT0.12: RRT 0.28: 0.38% AUC 0.73% AUC 0.53% AUC 0.08% AUC Total: 1.34% RRT0.27: RRT 0.27: Total: 1.73% AUC 0.97% AUC 0.52% AUC RRT 0.32: RRT 0.31:0.56% AUC 0.07% AUC RRT 0.44: RRT 0.36: 0.24% AUC 0.17% AUC RRT 0.51:Total: 2.66% 0.67% AUC RRT 0.60: 0.30% AUC RRT 0.76: 0.99% AUC RRT 0.88:1.32% AUC Total: 7.54% Cetirizine Assay 90%-110% Label 99.3% LC 97.1% LC98.6% LC NT 96.7% LC Claim Cetirizine Related Report individual RRT0.96: RRT 0.46: RRT 0.46: NT RRT 1.13: Substances % AUC, 0.05% AUC 0.08%AUC 0.08% AUC 0.96% AUC Report total, % AUC RRT 1.13: RRT 1.13: RRT1.13: Total: 0.96% AUC 0.14% AUC 0.69% AUC 0.70% AUC Total: 0.19% Total:0.77% Total: 0.78% Benzalkonium 50%-150% Label 96.7% LC NT NT NT 98.7%LC chloride Assay Claim Disodium Edetate 70%-120% Label 92.9% LC NT NTNT 90.4% LC Claim pH 6.5-7.8 7.1 7.1 7.1 NT 7.0 Osmolality Reportresults 272 mOsm/Kg 273 mOsm/Kg 272 mOsm/Kg NT 274 mOsm/Kg RH = relativehumidity, LC = label claim, AUC = area under curve, NT = not tested.*The low assay values were attributed to the inverted orientation inwhich the stability samples were stored. Samples stored in the uprightorientation were tested at the 2-week time point and subsequent timepoints, as reflected in the data shown.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1.-5. (canceled)
 6. A topical ophthalmic formulation comprisingcetirizine hydrochloride or dihydrochloride in an amount of 0.05% to0.5% (w/v) calculated as cetirizine free base, wherein cetirizine is theonly active agent in the formulation and the cetirizine is formulated ina vehicle comprising (a) a demulcent and/or viscosity enhancing polymer,(b) a preservative and (c) water, wherein the formulation has a pH ofabout 5.5 to 7.5, a viscosity of from 1-50 centipoise and an osmolalityof about 225-400 mOsm/kg, and wherein the formulation does not contain acyclodextrin.
 7. The topical ophthalmic formulation of claim 1, whereinthe cetirizine hydrochloride or dihydrochloride is present in an amountof 0.1% to 0.25% (w/v) calculated as cetirizine free base.
 8. Thetopical ophthalmic formulation of claim 1, wherein the formulation hasan osmolality of 280-320 mOsm/kg.
 9. The topical ophthalmic formulationof claim 1, wherein the formulation has a pH of about 6.0 to 7.0. 10.The topical ophthalmic formulation of claim 1, wherein the preservativecomprises benzalkonium chloride.
 11. The topical ophthalmic formulationof claim 1, wherein the viscosity is from 5-30 centipoise.
 12. Thetopical ophthalmic formulation of claim 1, wherein the demulcent and/orviscosity enhancing polymer comprises one or more members selected fromthe group consisting of a cellulose derivative, dextran, gelatin, apolyol and a carbomer.
 13. The topical ophthalmic formulation of claim12, wherein the cellulose derivative comprises one or more membersselected from the group consisting of carboxymethycellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose andmethylcelluose.
 14. The topical ophthalmic formulation of claim 12,wherein the polyol comprises one or more members selected from the groupconsisting of glycerin, polyethylene glycol, polysorbate, propyleneglycol, polyvinyl alcohol and povidone.
 15. The topical ophthalmicformulation of claim 6, wherein the formulation further comprises achelating agent.
 16. The topical ophthalmic formulation of claim 15,wherein the chelating agent comprises edetate disodium.